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ONKOSIGHT ADVANCEDTM NEXT GENERATION SEQUENCING

Introducing OnkoSight AdvancedTM . Empowering physicians with Advanced Genetic Sequencing to improve cancer patient management.

OnkoSight AdvancedTM is a next-generation sequencing (NGS) assay that enables cutting edge DNA mutational profiling of tumor samples. OnkoSight AdvancedTM focuses on only actionable mutations in common cancers. This targeted approach helps personalize patient treatment and management while greatly reducing the number of unclear variants that often occur in the results of broader NGS panels.

Genes included on OnkoSight AdvancedTM NGS panels are those with clear therapeutic, diagnostic, or prognostic value and those for which there are late-stage clinical trials available. National guidelines-recommended genes are included on each tumor-specific panel.

Critical genomic biomarkers relevant to immunotherapy; Tumor Mutation Burden (TMB) and Microsatellite Instability (MSI) are also reported with every OnkoSight AdvancedTM analysis.

Entire exonic coding regions and selected introns are broadly covered among genes targeted for analysis. Coverage of whole exonic coding regions represents an improvement over targeted hotspot approaches, and minimizes the risk of potential false negatives due to lack of coverage across clinically relevant genomic loci.

Click on a gene below to learn more

SOLID TUMOR NGS PANEL

OnkoSight AdvancedTM Colorectal Cancer Panel (29 genes), TMB and
MSI
Test Code: TH50-8

AKT1APCBRAFEGFREPCAMERBB2ERBB4FGFR1FGFR2
FGFR3FGFR4HRASKRASMETMAP2K1MLH1MSH2MSH6
NRASNTRK1PIK3CAPMS2POLD1POLEPTENSMAD4STK11
TERTTP53
Gene:
AKT1
Clinical Utility:
AKT1 mutations may predict response to AKT1/mTOR inhibitors.
Gene:
APC
Clinical Utility:
Tumor suppressor. Promotes rapid degradation of CTNNB1 and participates in Wnt signaling as a negative regulator. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells.
Gene:
BRAF
Clinical Utility:
Some mutations in BRAF predict response to RAF inhibitors in a variety of solid tumors. Therapies targeting BRAF V600-mutated melanoma (vemurafenib, dabrafenib, and trametinib) have been approved by the FDA. BRAF V600E is a negative prognostic marker in colorectal cancers, with resistance to anti-EGFR therapy in some clinical settings. In CNS neoplasms, BRAF V600E mutations are rarely found in adult gliomas with only 1% to 2 % mutated samples in glioblastomas and 2% to 5% in low grade adult gliomas. Even though a clear prognostic difference could not be established yet, BRAF V600E mutant glioblastomas have some distinct histopathological and molecular features. BRAF mutations are in most instances mutually exclusive to canonical IDH mutations.
Gene:
EGFR
Clinical Utility:
EGFR belongs to a family of four tyrosine kinases that encompasses ErbB1 (EGFR, HER1), ErbB2 (Her-2, Neu), ErbB3 (Her-3) and ErbB4 (Her-4). Amplifications and mutations in EGFR (HER1) were detected in 45–57% of GBM cases, indicating a causal role in the pathogenesis of GBM. EGFRs induce proliferation and have been implied in glioblastoma pathogenesis and resistance to treatment. EGFR is considered a potential therapeutic target for anti-EGFR therapy in triple-negative breast cancer (TNBC). Sensitizing EGFR mutations predict response to EGFR TKIs in NSCLC, including FDA-approved TKIs (erlotinib, gefitinib and afatinib), while other mutations predict resistance to first and second generation TKIs.
Gene:
EPCAM
Clinical Utility:
The Epithelial Cell Adhesion Molecule (EpCAM) has been shown to be strongly expressed in human breast cancer and cancer stem cells and its overexpression has been supposed to support tumor progression and metastasis. Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. EPCAM overexpression may be correlated with the development of bone metastasis and worse biochemical recurrence free-survival of PCa.
Gene:
ERBB2
Clinical Utility:
Mutations in ERBB2 (HER2) are emerging targets associated with response to anti-HER2 antibody (trastuzumab) or TKI (afatinib) therapy in NSCLC. In breast cancer, ERBB2 over-expression or gene amplification is associated with response to established anti-HER2 targeted therapies. In CNS neoplasms, ErbB2/HER-2 mutation have been detected in 8–41% of glioblastoma cases.
Gene:
ERBB4
Clinical Utility:
The ErbB signalling network plays a crucial role in the growth and progression of several cancers, including colorectal cancer (CRC), and includes potentially drug-targetable genes. Oncogenic activation of the ErbB pathway by mutations and focal amplifications have emerged recently as an important predictive marker of the prognosis of CRC patients.
Gene:
FGFR1
Clinical Utility:
Amplification of the FGFR1 gene predicts response to FGFR inhibition in several malignancies.
Gene:
FGFR2
Clinical Utility:
Alterations of FGFR2, including amplification, rearrangements and point mutations, predict response to FGFR inhibition in several malignancies.
Gene:
FGFR3
Clinical Utility:
Alterations of FGFR3, including amplification, rearrangements and point mutations, predict response to FGFR inhibition in several malignancies.
Gene:
FGFR4
Clinical Utility:
FGF-1/-3/FGFR4 Signaling in Cancer-Associated Fibroblasts Promotes Tumor Progression in Colon Cancer Through Erk and MMP-7. The phosphorylation of FGFR4 enhanced the production of metalloproteinase (MMP)-7 and mitogen-activated protein kinase kinase (Mek)/extracellular signal-regulated kinase (Erk), which was accompanied by excessive vessel generation and cell proliferation.
Gene:
HRAS
Clinical Utility:
RAS proteins (KRAS4A, KRAS4B, NRAS and HRAS) function as GDP–GTP-regulated binary on-off switches, which regulate cytoplasmic signaling networks that control diverse normal cellular processes. Gain-of-function missense mutations in RAS genes are found in ∼25% of human cancers, prompting interest in identifying anti-RAS therapeutic strategies for cancer treatment. RAS mutations have a high positive predictive value for malignancy in thyroid tumors, and aid in diagnosis of follicular thyroid lesions.
Gene:
KRAS
Clinical Utility:
KRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab). In NSCLC, KRAS mutations are associated with primary EGFR TKI resistance. In breast cancer, KRAS mRNA expression was found to be an independent prognostic factor. Prognostic role of KRAS mRNA expression was effective only in luminal A subtype breast cancer.
Gene:
MET
Clinical Utility:
MET alterations in solid tumors, including amplification and mutations, may predict response to MET inhibitors. MET amplification has been associated with acquired resistance to anti-EGFR TKIs in lung cancer.
Gene:
MAP2K1
Clinical Utility:
MAP2K1 mutations may confer resistance to BRAF and MEK inhibitors.
Gene:
MLH1
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. DNA mismatch repair (MMR) overexpression is common in prostate cancer and is linked to poor outcome as well as features indicating genetic instability. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors, whereas others have reported somatic hypermethylation of the MLH1 gene promoter, which is associated with MLH1 gene inactivation, in as many as 52% of colon tumors. Microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest
potential vulnerability to PD-1 inhibitors.
Gene:
MSH2
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer; Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
Gene:
MSH6
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. MSH6 is associated with an increased risk for breast cancer, and should be considered when ordering genetic testing for individuals who have a personal and/or family history of breast cancer.
Gene:
NRAS
Clinical Utility:
Mutations and overexpression of the neuroblastoma RAS viral (v‐ras) oncogene homolog (NRAS) are found across multiple tumor types and are common in highly metastatic cancers such as tumors of unknown primary, melanomas, and sarcomas that display a striking propensity for lung metastasis. Clinical studies suggest that patients with NRAS‐mutant or amplified tumors suffer from more aggressive disease than patients with wild‐type NRAS alleles.NRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab), and may predict response to MEK inhibitors in metastatic melanoma.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PIK3CA
Clinical Utility:
Mutations in PIK3CA may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
PMS2
Clinical Utility:
Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors. Additionally, lynch syndrome patients with PMS2 mutations may be at a higher risk of developing breast cancer. In prostate cancer, PMS2 plays a tumor suppresor role by enhancing apoptosis in prostate cancer cells.
Gene:
POLD1
Clinical Utility:
POLE/POLD1 gene variants have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutational burden (TMB), an effective indicator for response prediction in immunotherapy.
Gene:
POLE
Clinical Utility:
POLE/POLD1 gene variants have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutational burden (TMB), an effective indicator for response prediction in immunotherapy.
Gene:
PTEN
Clinical Utility:
Mutations in PTEN may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
SMAD4
Clinical Utility:
A tumor suppressor gene found in at least 26 types of cancer, with higher frequencies in GI tract cancers, such as esophagus, stomach, pancrease and colorectal cancers. Additionally, loss of SMAD4 in tumors affects cancer progression and therapy, such as reduced response to adjuvant chemotherapy.
Gene:
STK11
Clinical Utility:
STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. In one clinical study, it was found that STK11/LKB1 alterations is the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Mutations in this gene have been associated with Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by the growth of polyps in the gastrointestinal tract, pigmented macules on the skin and mouth, and other neoplasms. Several published reports have demonstrated the PJS predisposes carriers to cancers of the gastrointestinal tract, as well as susceptibility to a variety of tumors.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival
compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
TP53
Clinical Utility:
Somatic mutations in the TP53 gene are found in the majority of human cancers, and are generally associated with adverse prognostic characteristics in a number of tumor types.
Gene:
APC
Clinical Utility:
Tumor suppressor. Promotes rapid degradation of CTNNB1 and participates in Wnt signaling as a negative regulator. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells.
Gene:
ATRX
Clinical Utility:
ATRX mutations in glioma are strongly associated with IDH mutations, and are nearly always mutually exclusive with 1p/19q codeletion. ATRX deficiency, coupled with IDH mutations, is typical of astrocytoma.
Gene:
BRAF
Clinical Utility:
Some mutations in BRAF predict response to RAF inhibitors in a variety of solid tumors. Therapies targeting BRAF V600-mutated melanoma (vemurafenib, dabrafenib, and trametinib) have been approved by the FDA. BRAF V600E is a negative prognostic marker in colorectal cancers, with resistance to anti-EGFR therapy in some clinical settings. In CNS neoplasms, BRAF V600E mutations are rarely found in adult gliomas with only 1% to 2 % mutated samples in glioblastomas and 2% to 5% in low grade adult gliomas. Even though a clear prognostic difference could not be established yet, BRAF V600E mutant glioblastomas have some distinct histopathological and molecular features. BRAF mutations are in most instances mutually exclusive to canonical IDH mutations.
Gene:
CDKN2A
Clinical Utility:
Loss of CDKN2A is common in lymphoid neoplasms, has prognostic implications in some malignancies, and presents a therapeutic target for CDK4/6 inhibitors.
Gene:
CTNNB1
Clinical Utility:
Activating CTNNB1 mutations may predict response to WNT inhibitors.
Gene:
EGFR
Clinical Utility:
EGFR belongs to a family of four tyrosine kinases that encompasses ErbB1 (EGFR, HER1), ErbB2 (Her-2, Neu), ErbB3 (Her-3) and ErbB4 (Her-4). Amplifications and mutations in EGFR (HER1) were detected in 45–57% of GBM cases, indicating a causal role in the pathogenesis of GBM. EGFRs induce proliferation and have been implied in glioblastoma pathogenesis and resistance to treatment. EGFR is considered a potential therapeutic target for anti-EGFR therapy in triple-negative breast cancer (TNBC). Sensitizing EGFR mutations predict response to EGFR TKIs in NSCLC, including FDA-approved TKIs (erlotinib, gefitinib and afatinib), while other mutations predict resistance to first and second generation TKIs.
Gene:
ERBB2
Clinical Utility:
Mutations in ERBB2 (HER2) are emerging targets associated with response to anti-HER2 antibody (trastuzumab) or TKI (afatinib) therapy in NSCLC. In breast cancer, ERBB2 over-expression or gene amplification is associated with response to established anti-HER2 targeted therapies. In CNS neoplasms, ErbB2/HER-2 mutation have been detected in 8–41% of glioblastoma cases.
Gene:
H3F3A
Clinical Utility:
Mutations in H3F3A, which encodes histone H3.3, commonly occur at high frequency in pediatric glioblastoma and bone malignancies. Additionally, H3F3A K27M substitutions occur in gliomas that arise at midline locations (eg, pons, thalamus, spine); moreover, this substitution occurs mainly in tumors in children and adolescents. More than 80% of giant cell tumors harbored H3F3A mutations at the codon Gly34, about 95% of which were p.G34W resulting from a GGG>TGG nucleotide alteration. Given their high prevalence in giant cell tumor of bone and near non-existence among potential mimics, H3F3A G34 mutations could serve as a useful diagnostic adjunct.
Gene:
H3F3B
Clinical Utility:
Histone H3 encoding genes, particularly H3F3A and H3F3B, the genes encoding the variant histone H3.3, are mutated at high frequency in pediatric brain and bone malignancies. Mutations in H3F3A, which encodes histone H3.3, commonly occur at high frequency in pediatric glioblastoma and bone malignancies. Additionally, H3F3A K27M substitutions occur in gliomas that arise at midline locations (eg, pons, thalamus, spine); moreover, this substitution occurs mainly in tumors in children and adolescents. More than 80% of giant cell tumors harbored H3F3A mutations at the codon Gly34, about 95% of which were p.G34W resulting from a GGG>TGG nucleotide alteration. Given their high prevalence
in giant cell tumor of bone and near non-existence among potential mimics, H3F3A G34 mutations could serve as a useful diagnostic adjunct.
Gene:
H3F3C
Clinical Utility:
Mutations in H3F3A, which encodes histone H3.3, commonly occur at high frequency in pediatric glioblastoma and bone malignancies. Additionally, H3F3A K27M substitutions occur in gliomas that arise at midline locations (eg, pons, thalamus, spine); moreover, this substitution occurs mainly in tumors in children and adolescents. More than 80% of giant cell tumors harbored H3F3A mutations at the codon Gly34, about 95% of which were p.G34W resulting from a GGG>TGG nucleotide alteration. Given their high prevalence in giant cell tumor of bone and near non-existence among potential mimics, H3F3A G34 mutations could serve as a useful diagnostic adjunct.
Gene:
HIST1H3B
Clinical Utility:
HIST1H3B K27M mutation is associated with a less aggressive behavior in Diffuse intrinsic pontine glioma (DIPG).
Gene:
HIST1H3C
Clinical Utility:
Useful in a specific subgroup of patients with neuroblastoma for predicting survival. HIST1H3C methylation is associated with both overall survival and event-free survival
Gene:
IDH1
Clinical Utility:
IDH (IDH1 and IDH2) mutations are more prevalent in low grade diffuse gliomas and in secondary glioblastomas, they are associated with improved prognosis in low grade gliomas, and may predict response to therapy (IDH inhibitors, temolozomide). In acute myeloid leukemia (AML), somatic mutations in IDH1 and IDH2 are highly recurrent and are almost exclusively heterozygous and occur more frequently in AML in normal cytogenetics.
Gene:
IDH2
Clinical Utility:
IDH (IDH1 and IDH2) mutations are more prevalent in low grade diffuse gliomas and in secondary glioblastomas, they are associated with improved prognosis in low grade gliomas, and may predict response to therapy (IDH inhibitors, temolozomide). In acute myeloid leukemia (AML), somatic mutations in IDH1 and IDH2 are highly recurrent and are almost exclusively heterozygous and occur more frequently in AML in normal cytogenetics.
Gene:
MYC
Clinical Utility:
Activates the transcription of growth-related genes. Binds to the VEGFA promoter, promoting VEGFA production and subsequent sprouting angiogenesis. Regulator of somatic reprogramming, controls self-renewal of embryonic stem cells. Functions with TAF6L to activate target gene expression through RNA polymerase II pause release.
Gene:
NF1
Clinical Utility:
The nuclear factor I (NFI) is a family of transcription factors consisting of four distinct but closely related genes, NFIA, NFIB, NFIC and NFIX. Recent study results have shown that NFI family may play a critical role in the progression of various human tumors and have been identified as
key tumor suppressors and oncogenes for many cancers.
Gene:
NF2
Clinical Utility:
Mutation of NF2 results in the clinical tumor prone syndrome, neurofibromatosis type 2 (NF2), characterized by the development of multiple intracranial and spinal tumors, including schwannomas, meningioma, and ependymomas.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PDGFRA
Clinical Utility:
PDGFRA mutations predict response to TKIs (imatinib, sunitinib).
Gene:
PIK3CA
Clinical Utility:
Mutations in PIK3CA may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
PTEN
Clinical Utility:
Mutations in PTEN may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
SMARCA4
Clinical Utility:
SMARCA4 (BRG1), a central ATPase of BAF complexes, is the most frequently mutated Snf2-like gene in human cancer, and has been identified as a major tumor suppressor in pan-cancer studies. Loss of function mutations of SMARCA4 are enriched in diverse cancer types, contributing to a range of cancers including those of the lung, ovaries, skin, thoracic sarcoma, and lymphomas. SMARCA4 inactivation is especially common in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).
Gene:
SMARCB1
Clinical Utility:
MARCB1/INI1 is one of the core subunit proteins of the ATP-dependent SWI/SNF chromatin remodeling complex, and is identified as a potent and bona fide tumor suppressor. Interactions have been demonstrated between SMARCB1/INI1 and key proteins in various pathways related to tumor proliferation and progression: the p16-RB pathway, WNT signaling pathway, sonic hedgehog signaling pathway and Polycomb pathway.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival
compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
TP53
Clinical Utility:
Somatic mutations in the TP53 gene are found in the majority of human cancers, and are generally associated with adverse prognostic characteristics in a number of tumor types.
Gene:
VHL
Clinical Utility:
VHL mutations predispose to the development of a variety of tumours (most commonly retinal and central nervous system haemangioblastomas, clear cell renal carcinoma and phaeochromocytomas). Central nervous system hemangioblastoma (CHB) is the most common manifestation of VHL disease. The germline mutations in the VHL tumor suppressor gene are responsible for the inherited cancer predisposition syndrome or Von-Hippel-Lindau (VHL) disease.

OnkoSight AdvancedTM CNS Tumor Panel (26 genes), TMB and MSI
Test Code: TH57-3

APCATRXBRAFCDKN2ACTNNB1EGFRERBB2H3F3AH3F3B
H3F3CHIST1H3BHIST1H3CIDH1IDH2MYCNF1NF2NTRK1
PDGFRAPIK3CAPTENSMARCA4SMARCB1TERTTP53VHL
Gene:
APC
Clinical Utility:
Tumor suppressor. Promotes rapid degradation of CTNNB1 and participates in Wnt signaling as a negative regulator. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells.
Gene:
BRAF
Clinical Utility:
Some mutations in BRAF predict response to RAF inhibitors in a variety of solid tumors. Therapies targeting BRAF V600-mutated melanoma (vemurafenib, dabrafenib, and trametinib) have been approved by the FDA. BRAF V600E is a negative prognostic marker in colorectal cancers, with resistance to anti-EGFR therapy in some clinical settings. In CNS neoplasms, BRAF V600E mutations are rarely found in adult gliomas with only 1% to 2 % mutated samples in glioblastomas and 2% to 5% in low grade adult gliomas. Even though a clear prognostic difference could not be established yet, BRAF V600E mutant glioblastomas have some distinct histopathological and molecular features. BRAF mutations are in most instances mutually exclusive to canonical IDH mutations.
Gene:
EGFR
Clinical Utility:
EGFR belongs to a family of four tyrosine kinases that encompasses ErbB1 (EGFR, HER1), ErbB2 (Her-2, Neu), ErbB3 (Her-3) and ErbB4 (Her-4). Amplifications and mutations in EGFR (HER1) were detected in 45–57% of GBM cases, indicating a causal role in the pathogenesis of GBM. EGFRs induce proliferation and have been implied in glioblastoma pathogenesis and resistance to treatment. EGFR is considered a potential therapeutic target for anti-EGFR therapy in triple-negative breast cancer (TNBC). Sensitizing EGFR mutations predict response to EGFR TKIs in NSCLC, including FDA-approved TKIs (erlotinib, gefitinib and afatinib), while other mutations predict resistance to first and second generation TKIs.
Gene:
EPCAM
Clinical Utility:
The Epithelial Cell Adhesion Molecule (EpCAM) has been shown to be strongly expressed in human breast cancer and cancer stem cells and its overexpression has been supposed to support tumor progression and metastasis. Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. EPCAM overexpression may be correlated with the development of bone metastasis and worse biochemical recurrence free-survival of PCa.
Gene:
ERBB2
Clinical Utility:
Mutations in ERBB2 (HER2) are emerging targets associated with response to anti-HER2 antibody (trastuzumab) or TKI (afatinib) therapy in NSCLC. In breast cancer, ERBB2 over-expression or gene amplification is associated with response to established anti-HER2 targeted therapies. In CNS neoplasms, ErbB2/HER-2 mutation have been detected in 8–41% of glioblastoma cases.
Gene:
ERBB4
Clinical Utility:
The ErbB signalling network plays a crucial role in the growth and progression of several cancers, including colorectal cancer (CRC), and includes potentially drug-targetable genes. Oncogenic activation of the ErbB pathway by mutations and focal amplifications have emerged recently as an important predictive marker of the prognosis of CRC patients.
Gene:
FGFR1
Clinical Utility:
Amplification of the FGFR1 gene predicts response to FGFR inhibition in several malignancies.
Gene:
FGFR2
Clinical Utility:
Alterations of FGFR2, including amplification, rearrangements and point mutations, predict response to FGFR inhibition in several malignancies.
Gene:
FGFR3
Clinical Utility:
Alterations of FGFR3, including amplification, rearrangements and point mutations, predict response to FGFR inhibition in several malignancies.
Gene:
FGFR4
Clinical Utility:
FGF-1/-3/FGFR4 Signaling in Cancer-Associated Fibroblasts Promotes Tumor Progression in Colon Cancer Through Erk and MMP-7. The phosphorylation of FGFR4 enhanced the production of metalloproteinase (MMP)-7 and mitogen-activated protein kinase kinase (Mek)/extracellular signal-regulated kinase (Erk), which was accompanied by excessive vessel generation and cell proliferation.
Gene:
HRAS
Clinical Utility:
RAS proteins (KRAS4A, KRAS4B, NRAS and HRAS) function as GDP–GTP-regulated binary on-off switches, which regulate cytoplasmic signaling networks that control diverse normal cellular processes. Gain-of-function missense mutations in RAS genes are found in ∼25% of human cancers, prompting interest in identifying anti-RAS therapeutic strategies for cancer treatment. RAS mutations have a high positive predictive value for malignancy in thyroid tumors, and aid in diagnosis of ollicular thyroid lesions.
Gene:
KRAS
Clinical Utility:
KRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab). In NSCLC, KRAS mutations are associated with primary EGFR TKI resistance. In breast cancer, KRAS mRNA expression was found to be an independent prognostic factor. Prognostic role of KRAS mRNA expression was effective only in luminal A subtype breast cancer.
Gene:
MET
Clinical Utility:
MET alterations in solid tumors, including amplification and mutations, may predict response to MET inhibitors. MET amplification has been associated with acquired resistance to anti-EGFR TKIs in lung cancer.
Gene:
MAP2K1
Clinical Utility:
MAP2K1 mutations may confer resistance to BRAF and MEK inhibitors.
Gene:
MLH1
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. DNA mismatch repair (MMR) overexpression is common in prostate cancer and is linked to poor outcome as well as features indicating genetic instability. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors, whereas others have reported somatic hypermethylation of the MLH1 gene promoter, which is associated with MLH1 gene inactivation, in as many as 52% of colon tumors. Microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest
potential vulnerability to PD-1 inhibitors.
Gene:
MSH2
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer; Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
Gene:
MSH6
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. MSH6 is associated with an increased risk for breast cancer, and should be considered when ordering genetic testing for individuals who have a personal and/or family history of breast cancer.
Gene:
NRAS
Clinical Utility:
Mutations and overexpression of the neuroblastoma RAS viral (v‐ras) oncogene homolog (NRAS) are found across multiple tumor types and are common in highly metastatic cancers such as tumors of unknown primary, melanomas, and sarcomas that display a striking propensity for lung metastasis. Clinical studies suggest that patients with NRAS‐mutant or amplified tumors suffer from more aggressive disease than patients with wild‐type NRAS alleles.NRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab), and may predict response to MEK inhibitors in metastatic melanoma.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PIK3CA
Clinical Utility:
Mutations in PIK3CA may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
PMS2
Clinical Utility:
Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors. Additionally, lynch syndrome patients with PMS2 mutations may be at a higher risk of developing breast cancer. In prostate cancer, PMS2 plays a tumor suppresor role by enhancing apoptosis in prostate cancer cells.
Gene:
POLD1
Clinical Utility:
POLE/POLD1 gene variants have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutational burden (TMB), an effective indicator for response prediction in immunotherapy.
Gene:
POLE
Clinical Utility:
POLE/POLD1 gene variants have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutational burden (TMB), an effective indicator for response prediction in immunotherapy.
Gene:
PTEN
Clinical Utility:
Mutations in PTEN may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
SMAD4
Clinical Utility:
A tumor suppressor gene found in at least 26 types of cancer, with higher frequencies in GI tract cancers, such as esophagus, stomach, pancrease and colorectal cancers. Additionally, loss of SMAD4 in tumors affects cancer progression and therapy, such as reduced response to adjuvant chemotherapy.
Gene:
STK11
Clinical Utility:
STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. In one clinical study, it was found that STK11/LKB1 alterations is the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Mutations in this gene have been associated with Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by the growth of polyps in the gastrointestinal tract, pigmented macules on the skin and mouth, and other neoplasms. Several published reports have demonstrated the PJS predisposes carriers to cancers of the gastrointestinal tract, as well as susceptibility to a variety of tumors.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival
compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
TP53
Clinical Utility:
Somatic mutations in the TP53 gene are found in the majority of human cancers, and are generally associated with adverse prognostic characteristics in a number of tumor types.
Gene:
APC
Clinical Utility:
Tumor suppressor. Promotes rapid degradation of CTNNB1 and participates in Wnt signaling as a negative regulator. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells
Gene:
ATRX
Clinical Utility:
ATRX mutations in glioma are strongly associated with IDH mutations, and are nearly always mutually exclusive with 1p/19q codeletion. ATRX deficiency, coupled with IDH mutations, is typical of astrocytoma.
Gene:
BRAF
Clinical Utility:
Some mutations in BRAF predict response to RAF inhibitors in a variety of solid tumors. Therapies targeting BRAF V600-mutated melanoma (vemurafenib, dabrafenib, and trametinib) have been approved by the FDA. BRAF V600E is a negative prognostic marker in colorectal cancers, with resistance to anti-EGFR therapy in some clinical settings. In CNS neoplasms, BRAF V600E mutations are rarely found in adult gliomas with only 1% to 2 % mutated samples in glioblastomas and 2% to 5% in low grade adult gliomas. Even though a clear prognostic difference could not be established yet, BRAF V600E mutant glioblastomas have some distinct histopathological and molecular features. BRAF mutations are in most instances mutually exclusive to canonical IDH mutations.
Gene:
CDKN2A
Clinical Utility:
Loss of CDKN2A is common in lymphoid neoplasms, has prognostic implications in some malignancies, and presents a therapeutic target for CDK4/6 inhibitors.
Gene:
CTNNB1
Clinical Utility:
Activating CTNNB1 mutations may predict response to WNT inhibitors.
Gene:
EGFR
Clinical Utility:
EGFR belongs to a family of four tyrosine kinases that encompasses ErbB1 (EGFR, HER1), ErbB2 (Her-2, Neu), ErbB3 (Her-3) and ErbB4 (Her-4). Amplifications and mutations in EGFR (HER1) were detected in 45–57% of GBM cases, indicating a causal role in the pathogenesis of GBM. EGFRs induce proliferation and have been implied in glioblastoma pathogenesis and resistance to treatment. EGFR is considered a potential therapeutic target for anti-EGFR therapy in triple-negative breast cancer (TNBC). Sensitizing EGFR mutations predict response to EGFR TKIs in NSCLC, including FDA-approved TKIs (erlotinib, gefitinib and afatinib), while other mutations predict resistance to first and second generation TKIs.
Gene:
ERBB2
Clinical Utility:
Mutations in ERBB2 (HER2) are emerging targets associated with response to anti-HER2 antibody (trastuzumab) or TKI (afatinib) therapy in NSCLC. In breast cancer, ERBB2 over-expression or gene amplification is associated with response to established anti-HER2 targeted therapies. In CNS neoplasms, ErbB2/HER-2 mutation have been detected in 8–41% of glioblastoma cases.
Gene:
H3F3A
Clinical Utility:
Mutations in H3F3A, which encodes histone H3.3, commonly occur at high frequency in pediatric glioblastoma and bone malignancies. Additionally, H3F3A K27M substitutions occur in gliomas that arise at midline locations (eg, pons, thalamus, spine); moreover, this substitution occurs mainly in tumors in children and adolescents. More than 80% of giant cell tumors harbored H3F3A mutations at
the codon Gly34, about 95% of which were p.G34W resulting from a GGG>TGG nucleotide alteration. Given their high prevalence in giant cell tumor of bone and near non-existence among potential mimics, H3F3A G34 mutations could serve as a useful diagnostic adjunct.
Gene:
H3F3B
Clinical Utility:
Histone H3 encoding genes, particularly H3F3A and H3F3B, the genes encoding the variant histone H3.3, are mutated at high frequency in pediatric brain and bone malignancies. Mutations in H3F3A, which encodes histone H3.3, commonly occur at high frequency in pediatric glioblastoma and bone malignancies. Additionally, H3F3A K27M substitutions occur in gliomas that arise at midline locations (eg, pons, thalamus, spine); moreover, this substitution occurs mainly in tumors in children and adolescents. More than 80% of giant cell tumors harbored H3F3A mutations at the codon Gly34, about 95% of which were p.G34W resulting from a GGG>TGG nucleotide alteration. Given their high prevalence in giant cell tumor of bone and near non-existence among potential mimics, H3F3A G34 mutations could serve as a useful diagnostic adjunct.
Gene:
H3F3C
Clinical Utility:
Mutations in H3F3A, which encodes histone H3.3, commonly occur at high frequency in pediatric glioblastoma and bone malignancies. Additionally, H3F3A K27M substitutions occur in gliomas that arise at midline locations (eg, pons, thalamus, spine); moreover, this substitution occurs mainly in tumors in children and adolescents. More than 80% of giant cell tumors harbored H3F3A mutations at
the codon Gly34, about 95% of which were p.G34W resulting from a GGG>TGG nucleotide alteration. Given their high prevalence in giant cell tumor of bone and near non-existence among potential mimics, H3F3A G34 mutations could serve as a useful diagnostic adjunct.
Gene:
HIST1H3B
Clinical Utility:
HIST1H3B K27M mutation is associated with a less aggressive behavior in Diffuse intrinsic pontine glioma (DIPG).
Gene:
HIST1H3C
Clinical Utility:
Useful in a specific subgroup of patients with neuroblastoma for predicting survival. HIST1H3C methylation is associated with both overall survival and event-free survival
Gene:
IDH1
Clinical Utility:
IDH (IDH1 and IDH2) mutations are more prevalent in low grade diffuse gliomas and in secondary glioblastomas, they are associated with improved prognosis in low grade gliomas, and may predict response to therapy (IDH inhibitors, temolozomide). In acute myeloid leukemia (AML), somatic mutations in IDH1 and IDH2 are highly recurrent and are almost exclusively heterozygous and occur more frequently in AML in normal cytogenetics.
Gene:
IDH2
Clinical Utility:
IDH (IDH1 and IDH2) mutations are more prevalent in low grade diffuse gliomas and in secondary glioblastomas, they are associated with improved prognosis in low grade gliomas, and may predict response to therapy (IDH inhibitors, temolozomide). In acute myeloid leukemia (AML), somatic mutations in IDH1 and IDH2 are highly recurrent and are almost exclusively heterozygous and occur more frequently in AML in normal cytogenetics.
Gene:
MYC
Clinical Utility:
Activates the transcription of growth-related genes. Binds to the VEGFA promoter, promoting VEGFA production and subsequent sprouting angiogenesis. Regulator of somatic reprogramming, controls self-renewal of embryonic stem cells. Functions with TAF6L to activate target gene expression through RNA polymerase II pause release.
Gene:
NF1
Clinical Utility:
The nuclear factor I (NFI) is a family of transcription factors consisting of four distinct but closely related genes, NFIA, NFIB, NFIC and NFIX. Recent study results have shown that NFI family may play a critical role in the progression of various human tumors and have been identified as key tumor suppressors and oncogenes for many cancers.
Gene:
NF2
Clinical Utility:
Mutation of NF2 results in the clinical tumor prone syndrome, neurofibromatosis type 2 (NF2), characterized by the development of multiple intracranial and spinal tumors, including schwannomas, meningioma, and ependymomas.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PDGFRA
Clinical Utility:
PDGFRA mutations predict response to TKIs (imatinib, sunitinib).
Gene:
PIK3CA
Clinical Utility:
Mutations in PIK3CA may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
PTEN
Clinical Utility:
Mutations in PTEN may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
SMARCA4
Clinical Utility:
SMARCA4 (BRG1), a central ATPase of BAF complexes, is the most frequently mutated Snf2-like gene in human cancer, and has been identified as a major tumor suppressor in pan-cancer studies. Loss of function mutations of SMARCA4 are enriched in diverse cancer types, contributing to a range of cancers including those of the lung, ovaries, skin, thoracic sarcoma, and lymphomas. SMARCA4 inactivation is especially common in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).
Gene:
SMARCB1
Clinical Utility:
MARCB1/INI1 is one of the core subunit proteins of the ATP-dependent SWI/SNF chromatin remodeling complex, and is identified as a potent and bona fide tumor suppressor. Interactions have been demonstrated between SMARCB1/INI1 and key proteins in various pathways related to tumor proliferation and progression: the p16-RB pathway, WNT signaling pathway, sonic hedgehog signaling pathway and Polycomb pathway.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival
compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
TP53
Clinical Utility:
Somatic mutations in the TP53 gene are found in the majority of human cancers, and are generally associated with adverse prognostic characteristics in a number of tumor types.
Gene:
VHL
Clinical Utility:
VHL mutations predispose to the development of a variety of tumours (most commonly retinal and central nervous system haemangioblastomas, clear cell renal carcinoma and phaeochromocytomas). Central nervous system hemangioblastoma (CHB) is the most common manifestation of VHL disease. The germline mutations in the VHL tumor suppressor gene are responsible for the inherited cancer predisposition syndrome or Von-Hippel-Lindau (VHL) disease.

OnkoSight AdvancedTM GIST Panel (9 genes), TMB and MSI
Test Code: TH58-1

BRAFKITNF1NTRK1PDGFRASDHASDHBSDHCSDHD
Gene:
BRAF
Clinical Utility:
Some mutations in BRAF predict response to RAF inhibitors in a variety of solid tumors. Therapies targeting BRAF V600-mutated melanoma (vemurafenib, dabrafenib, and trametinib) have been approved by the FDA. BRAF V600E is a negative prognostic marker in colorectal cancers, with resistance to anti-EGFR therapy in some clinical settings. In CNS neoplasms, BRAF V600E mutations are rarely found in adult gliomas with only 1% to 2 % mutated samples in glioblastomas and 2% to 5% in low grade adult gliomas. Even though a clear prognostic difference could not be established yet, BRAF V600E mutant glioblastomas have some distinct histopathological and molecular features. BRAF mutations are in most instances mutually exclusive to canonical IDH mutations.
Gene:
KIT
Clinical Utility:
In GISTs, KIT mutations predict response to TKIs (imatinib, sunitinib), with secondary mutations associated with resistance. In metastatic melanoma cases, limited response to imatinib has been reported.
Gene:
NF1
Clinical Utility:
The nuclear factor I (NFI) is a family of transcription factors consisting of four distinct but closely related genes, NFIA, NFIB, NFIC and NFIX. Recent study results have shown that NFI family may play a critical role in the progression of various human tumors and have been identified as
key tumor suppressors and oncogenes for many cancers.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PDGFRA
Clinical Utility:
PDGFRA mutations predict response to TKIs (imatinib, sunitinib).
Gene:
SDHA
Clinical Utility:
Mutations of genes encoding the subunits of the succinate dehydrogenase (SDH) complex were described in KIT/PDGFRA wild-type GIST separately in different reports. The SDH complex is comprised of or modified by proteins encoded by SDHA, SDHB, SDHC, SDHD, and SDHAF2. In GIST, alterations in SDH have most commonly been reported in SDHB, but also have been found in SDHC, SDHD, and, recently, SDHA. Germline mutations in SDHB and SDHC have been identified in SDH-deficient GIST but appear to account for <15% of cases.
Gene:
SDHB
Clinical Utility:
Mutations of genes encoding the subunits of the succinate dehydrogenase (SDH) complex were described in KIT/PDGFRA wild-type GIST separately in different reports. The SDH complex is comprised of or modified by proteins encoded by SDHA, SDHB, SDHC, SDHD, and SDHAF2. In GIST, alterations in SDH have most commonly been reported in SDHB, but also have been found in SDHC, SDHD, and, recently, SDHA. Germline mutations in SDHB and SDHC have been identified in SDH-deficient GIST but appear to account for <15% of cases.
Gene:
SDHC
Clinical Utility:
Mutations of genes encoding the subunits of the succinate dehydrogenase (SDH) complex were described in KIT/PDGFRA wild-type GIST separately in different reports. The SDH complex is comprised of or modified by proteins encoded by SDHA, SDHB, SDHC, SDHD, and SDHAF2. In GIST, alterations in SDH have most commonly been reported in SDHB, but also have been found in SDHC, SDHD, and, recently, SDHA. Germline mutations in SDHB and SDHC have been identified in SDH-deficient GIST but appear to account for <15% of cases.
Gene:
SDHD
Clinical Utility:
Mutations of genes encoding the subunits of the succinate dehydrogenase (SDH) complex were described in KIT/PDGFRA wild-type GIST separately in different reports. The SDH complex is comprised of or modified by proteins encoded by SDHA, SDHB, SDHC, SDHD, and SDHAF2. In GIST, alterations n SDH have most commonly been reported in SDHB, but also have been found in SDHC, SDHD, and, recently, SDHA. Germline mutations in SDHB and SDHC have been identified in SDH-deficient GIST but appear to account for <15% of cases.
Gene:
AKT1
Clinical Utility:
AKT1 mutations may predict response to AKT1/mTOR inhibitors.
Gene:
AR
Clinical Utility:
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and ZBTB7A that recruits NCOR1 and NCOR2 to the androgen response elements/ARE on target genes, negatively regulating androgen receptor signaling and androgen-induced cell proliferation
Gene:
ATM
Clinical Utility:
A DNA-damage response gene that is commonly mutated in cancer. Germline mutations in this gene are thought to contribute to breast cancer susceptibility, and PARP inhibition is currently being studied for it’s potential in treating these patients. In lymphoid neoplasms, somatic mutations of ATM occur frequently in mantle cell lymphomas (MCL), chronic lymphoblastic leukemia (CLL) and T-cell prolymphocytic leukemia (TPLL).
Gene:
BRCA1
Clinical Utility:
In advance disease setting, mutations in homologous recombination repair genes such as BRCA1 and BRCA2 suggest candidacy for platinum chemotherapy and PARP inhibitor trials.
Gene:
BRCA2
Clinical Utility:
In advance disease setting, mutations in homologous recombination repair genes such as BRCA1 and BRCA2 suggest candidacy for platinum chemotherapy and PARP inhibitor trials.
Gene:
CDH1
Clinical Utility:
Involved in mechanisms regulating cell-cell adhesions, mobility and proliferation of epithelial cells. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis
Gene:
CHEK2
Clinical Utility:
Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors
Gene:
EGFR
Clinical Utility:
EGFR belongs to a family of four tyrosine kinases that encompasses ErbB1 (EGFR, HER1), ErbB2 (Her-2, Neu), ErbB3 (Her-3) and ErbB4 (Her-4). Amplifications and mutations in EGFR (HER1) were detected in 45–57% of GBM cases, indicating a causal role in the pathogenesis of GBM. EGFRs induce proliferation and have been implied in glioblastoma pathogenesis and resistance to treatment. EGFR is considered a potential therapeutic target for anti-EGFR therapy in triple-negative breast cancer (TNBC). Sensitizing EGFR mutations predict response to EGFR TKIs in NSCLC, including FDA-approved TKIs (erlotinib, gefitinib and afatinib), while other mutations predict resistance to first and second generation TKIs.
Gene:
EPCAM
Clinical Utility:
The Epithelial Cell Adhesion Molecule (EpCAM) has been shown to be strongly expressed in human breast cancer and cancer stem cells and its overexpression has been supposed to support tumor progression and metastasis. Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. EPCAM overexpression may be correlated with the development of bone metastasis and worse biochemical recurrence free-survival of
PCa.
Gene:
ERBB2
Clinical Utility:
Mutations in ERBB2 (HER2) are emerging targets associated with response to anti-HER2 antibody (trastuzumab) or TKI (afatinib) therapy in NSCLC. In breast cancer, ERBB2 over-expression or gene amplification is associated with response to established anti-HER2 targeted therapies. In CNS neoplasms, ErbB2/HER-2 mutation have been detected in 8–41% of glioblastoma cases.
Gene:
ESR1
Clinical Utility:
Activating mutations in ESR1 are associated with acquired resistance to endocrine therapy in hormone-dependent metastatic breast cancer.
Gene:
FANCA
Clinical Utility:
The FANCA gene is one of the genes in which mutations lead to Fanconi anaemia, a rare autosomal recessive disorder characterised by congenital abnormalities, bone marrow failure, and predisposition to malignancy. FANCA is also a potential breast and ovarian cancer susceptibility
gene. Associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. Defects in genes involved in DNA damage repair (DDR) pathway are emerging as novel biomarkers and targets for new prostate cancer drug therapies.
Gene:
FGFR1
Clinical Utility:
Amplification of the FGFR1 gene predicts response to FGFR inhibition in several malignancies.
Gene:
FGFR2
Clinical Utility:
Alterations of FGFR2, including amplification, rearrangements and point mutations,
predict response to FGFR inhibition in several malignancies.
Gene:
FOXA1
Clinical Utility:
The expression of FOXA1 is directly related to the expression of Androgen Receptor (AR). Despite that, FOXA1 is found as superior predicting marker of recurrences compared to AR in Estrogen Receptor postiive (ER+) Breast Cancer patients.
Gene:
KRAS
Clinical Utility:
KRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab). In NSCLC, KRAS mutations are associated with primary EGFR TKI resistance. In breast cancer, KRAS mRNA expression was found to be an independent prognostic factor. Prognostic role of KRAS mRNA expression was effective only in luminal A subtype breast cancer.
Gene:
MLH1
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. DNA mismatch repair (MMR) overexpression is common in prostate cancer and is linked to poor outcome as well as features indicating genetic instability. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors, whereas others have reported somatic hypermethylation of the MLH1 gene promoter, which is associated with MLH1 gene inactivation, in as many as 52% of colon tumors. Microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest
potential vulnerability to PD-1 inhibitors.
Gene:
MSH2
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer; Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
Gene:
MSH6
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. MSH6 is associated with an increased risk for breast cancer, and should be considered when ordering genetic testing for individuals who have a personal and/or family history of breast cancer.
Gene:
NBN
Clinical Utility:
Nibrin, encoded by the NBN gene, participates in DNA repair. Mutations in the NBN gene lead to Nijemen breakage syndrome (NBS), which may result in several types of diseases, particularly susceptibility to cancer, including breast cancer. Polymorphic variants and defective mutations occurring in the NBN gene increase the risk of breast cancer through the double-stranded break repair mechanism. NBN mutations/polymorphisms were also found in sporadic melanomas and basal cell carcinoma. In addition, NBS patients exhibited various skin abnormalities including abnormal pigmentation of the skin, sparse and thin hairs, and less frequently cutaneous non caseating granulomas porokeratosis, and depigmentation. Altogether these findings suggest a key function of NBN in skin homeostasis.
Gene:
MYC
Clinical Utility:
Activates the transcription of growth-related genes. Binds to the VEGFA promoter, promoting VEGFA production and subsequent sprouting angiogenesis. Regulator of somatic reprogramming, controls self-renewal of embryonic stem cells. Functions with TAF6L to activate target gene expression through RNA polymerase II pause release.
Gene:
NF1
Clinical Utility:
The nuclear factor I (NFI) is a family of transcription factors consisting of four distinct but closely related genes, NFIA, NFIB, NFIC and NFIX. Recent study results have shown that NFI family may play a critical role in the progression of various human tumors and have been identified as
key tumor suppressors and oncogenes for many cancers.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PALB2
Clinical Utility:
PALB2 (Partner and Localizer of Breast Cancer 2 (BRCA2)) plays an important role in maintaining genome integrity through its role in the Fanconi anemia (FA) and homologous recombination (HR) DNA repair pathways. PALB2 has emerged as a pivotal tumor suppressor protein associated to
hereditary cancer susceptibility to breast and pancreatic cancers. In advanced disease setting for prostate cancer, mutations in homologous recombination repair genes (eg, BRCA1, BRCA2, ATM, CHEK2, PALB2) suggest candidacy for platinum chemotherapy and PARP inhibitor trials.
Gene:
PIK3CA
Clinical Utility:
Mutations in PIK3CA may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
PMS2
Clinical Utility:
Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors. Additionally, lynch syndrome patients with PMS2 mutations may be at a higher risk of developing breast cancer. In prostate cancer, PMS2 plays a tumor suppresor role by enhancing apoptosis in prostate cancer cells.
Gene:
POLE
Clinical Utility:
POLE/POLD1 gene variants have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutational burden (TMB), an effective indicator for response prediction in immunotherapy.
Gene:
PTEN
Clinical Utility:
Mutations in PTEN may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
RAD51D
Clinical Utility:
Recent data indicate that men with prostate cancer may have germline mutations in 1 of 16 DNA repair genes including RAD51D (0.4%). Men with these inherited syndromes have an increased risk for prostate cancer. RAD51D germline mutations have been recently associated with ovarian and breast cancer.
Gene:
RB1
Clinical Utility:
Retinoblastoma 1 (RB1) is a gene that encodes a protein that is a negative regulator of the cell cycle as well as a tumor suppressor. Missense mutations, nonsense mutations, silent mutations, frameshift deletions and insertions, and in-frame deletions are observed in cancers such as
cancers of the fallopian tubes, cancers of the eye, and intestinal cancer. RB1 is altered in 4.03% of all cancers with lung adenocarcinoma, breast invasive ductal carcinoma, small cell lung carcinoma,  bladder urothelial carcinoma, and colon adenocarcinoma having the greatest prevalence of alterations
Gene:
TBX3
Clinical Utility:
The T-box transcription factor 3 (TBX3), a member of this T-box factors family, is expressed in several tissues and plays critical roles in, among other structures, the heart, mammary gland and limbs and haploinsufficiency of the human TBX3 gene is the genetic basis for the autosomal
dominant disorder, ulnar-mammary syndrome. Overexpression of TBX3 on the other hand has been linked to several cancers including melanoma, breast, pancreatic, liver, lung, head and neck, ovarian, bladder carcinomas and a number of sarcoma subtypes. Furthermore, there is strong evidence that TBX3 promotes oncogenesis by impacting proliferation, tumour formation, metastasis as well as cell survival and drug resistance.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
TP53
Clinical Utility:
Somatic mutations in the TP53 gene are found in the majority of human cancers, and are generally associated with adverse prognostic characteristics in a number of tumor types.
Gene:
BAP1
Clinical Utility:
Mutation cause Tumor predisposition syndrome (TPDS). A condition characterized by predisposition to develop a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma, cutaneous melanoma, malignant mesothelioma on exposure to asbestos, lung adenocarcinoma and meningioma.
Gene:
BRAF
Clinical Utility:
Some mutations in BRAF predict response to RAF inhibitors in a variety of solid tumors. Therapies targeting BRAF V600-mutated melanoma (vemurafenib, dabrafenib, and trametinib) have been approved by the FDA. BRAF V600E is a negative prognostic marker in colorectal cancers, with resistance to anti-EGFR therapy in some clinical settings. In CNS neoplasms, BRAF V600E mutations are rarely found in adult gliomas with only 1% to 2 % mutated samples in glioblastomas and 2% to 5% in low grade adult gliomas. Even though a clear prognostic difference could not be established yet, BRAF V600E mutant glioblastomas have some distinct histopathological and molecular features. BRAF mutations are in most instances mutually exclusive to canonical IDH mutations.
Gene:
CDK4
Clinical Utility:
Loss of CDKN2A is common in lymphoid neoplasms, has prognostic implications in some malignancies, and presents a therapeutic target for CDK4/6 inhibitors.
Gene:
CDKN2A
Clinical Utility:
Loss of CDKN2A is common in lymphoid neoplasms, has prognostic implications in some malignancies, and presents a therapeutic target for CDK4/6 inhibitors.
Gene:
CTNNB1
Clinical Utility:
Activating CTNNB1 mutations may predict response to WNT inhibitors.
Gene:
EIF1AX
Clinical Utility:
The EIF1AX gene encodes for the eukaryotic translation initiation factor 1A, x-linked protein. This protein plays a role in the initiation of translation of mRNA to protein. In uveal melanoma, mutations in EIF1AX have been reported in the first two exons of the gene, which encode for
the unstructured N-terminal tail of the EIF1AX protein. EIF1AX mutations occur in approximately 17-24% of uveal melanomas and are usually not found in conjunction with SF3B1 or BAP1 mutations.
Gene:
GNA11
Clinical Utility:
Somatic mutations in either GNA11 or GNAQ genes are identified in majority of uveal melanoma cases.
Gene:
GNAQ
Clinical Utility:
Somatic mutations in either GNA11 or GNAQ genes are identified in the majority of uveal melanoma cases.
Gene:
GNAS
Clinical Utility:
Mutations are specific to uveal melanoma and other non-cutaneous melanomas, are not found in normal tissues, thus making them potential therapeutic targets.
Gene:
KIT
Clinical Utility:
In GISTs, KIT mutations predict response to TKIs (imatinib, sunitinib), with secondary mutations associated with resistance. In metastatic melanoma cases, limited response to imatinib has been reported.
Gene:
MAP2K1
Clinical Utility:
MAP2K1 mutations may confer resistance to BRAF and MEK inhibitors.
Gene:
MITF
Clinical Utility:
Plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1). Plays a critical role in the differentiation of various cell types, such as neural crest-derived melanocytes, mast cells, osteoclasts and optic
cup-derived retinal pigment epithelium.
Gene:
NBN
Clinical Utility:
Nibrin, encoded by the NBN gene, participates in DNA repair. Mutations in the NBN gene lead to Nijemen breakage syndrome (NBS), which may result in several types of diseases, particularly susceptibility to cancer, including breast cancer. Polymorphic variants and defective mutations
occurring in the NBN gene increase the risk of breast cancer through the double-stranded break repair mechanism. NBN mutations/polymorphisms were also found in sporadic melanomas and basal cell carcinoma. In addition, NBS patients exhibited various skin abnormalities including abnormal pigmentation of the skin, sparse and thin hairs, and less frequently cutaneous non caseating granulomas porokeratosis, and depigmentation. Altogether these findings suggest a key function of NBN in skin homeostasis.
Gene:
NF1
Clinical Utility:
The nuclear factor I (NFI) is a family of transcription factors consisting of four distinct but closely related genes, NFIA, NFIB, NFIC and NFIX. Recent study results have shown that NFI family may play a critical role in the progression of various human tumors and have been identified as
key tumor suppressors and oncogenes for many cancers.
Gene:
NRAS
Clinical Utility:
Mutations and overexpression of the neuroblastoma RAS viral (v‐ras) oncogene homolog (NRAS) are found across multiple tumor types and are common in highly metastatic cancers such as tumors of unknown primary, melanomas, and sarcomas that display a striking propensity for lung metastasis. Clinical studies suggest that patients with NRAS‐mutant or amplified tumors suffer from more aggressive disease than patients with wild‐type NRAS alleles.NRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab), and may predict response to MEK inhibitors in metastatic melanoma.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PDGFRA
Clinical Utility:
PDGFRA mutations predict response to TKIs (imatinib, sunitinib).
Gene:
PIK3CA
Clinical Utility:
Mutations in PIK3CA may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
PTEN
Clinical Utility:
Mutations in PTEN may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
RB1
Clinical Utility:
Retinoblastoma 1 (RB1) is a gene that encodes a protein that is a negative regulator of the cell cycle as well as a tumor suppressor. Missense mutations, nonsense mutations, silent mutations, frameshift deletions and insertions, and in-frame deletions are observed in cancers such as
cancers of the fallopian tubes, cancers of the eye, and intestinal cancer. RB1 is altered in 4.03% of all cancers with lung adenocarcinoma, breast invasive ductal carcinoma, small cell lung carcinoma, bladder urothelial carcinoma, and colon adenocarcinoma having the greatest prevalence of alterations
Gene:
SF3B1
Clinical Utility:
SF3B1 mutations were significantly associated with ER-positive disease, AKT1 mutations, and distinct copy number alterations. Additional profiling of hotspot mutations in a panel of special histological subtypes of breast cancer showed that 16% and 6% of papillary and mucinous
carcinomas of the breast harboured the SF3B1 K700E mutation. In uveal melanoma, SF3B1 mutations are generally associated with tumors having a favorable prognosis. In additon, SF3B1 R625 mutations in conjunction with GNAQ and GNA11 mutations are a genetic marker of malignancy in blue nevus-like melanocytic proliferations. In Chronic lymphocytic leukemia (CLL), SF3B1, a ubiquitously expressed splicing factor, has been found mutated in 5-17% of CLL cases, in which it is associated with a poor prognosis, reduced overall survival, and resistance to treatment with fludarabine.
Gene:
SMO
Clinical Utility:
The G protein-coupled receptor (GPCR) smoothened (SMO) is a key signaling component of the sonic hedgehog (Hh) pathway and a clinically validated target for cancer treatment. Currently FDA-approved SMO inhibitors are GDC-0449/Vismodegib and LDE225/Sonidegib.
Gene:
SRC
Clinical Utility:
SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) is an important driver of YAP/TAZ activity in human breast cancer and melanoma cells. SRC activation increased YAP/TAZ activity and the expression of YAP/TAZ-regulated genes.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
TP53
Clinical Utility:
Somatic mutations in the TP53 gene are found in the majority of human cancers, and are generally associated with adverse prognostic characteristics in a number of tumor types.

OnkoSight AdvancedTM Gynecologic Neoplasms Panel (33 genes), TMB
and MSI
Test Code: TH53-2

AKT1ARATMBRCA1BRCA2CDH1CHEK2EGFREPCAM
ERBB2ESR1FANCAFGFR1FGFR2FOXA1KRASMLH1MSH2
MSH6NBNMYCNF1NTRK1PALB2PIK3CAPMS2POLE
PTENRAD51DRB1TBX3TERTTP53
Gene:
BRAF
Clinical Utility:
Some mutations in BRAF predict response to RAF inhibitors in a variety of solid tumors. Therapies targeting BRAF V600-mutated melanoma (vemurafenib, dabrafenib, and trametinib) have been approved by the FDA. BRAF V600E is a negative prognostic marker in colorectal cancers, with resistance to anti-EGFR therapy in some clinical settings. In CNS neoplasms, BRAF V600E mutations are rarely found in adult gliomas with only 1% to 2 % mutated samples in glioblastomas and 2% to 5% in low grade adult gliomas. Even though a clear prognostic difference could not be established yet, BRAF V600E mutant glioblastomas have some distinct histopathological and molecular features. BRAF mutations are in most instances mutually exclusive to canonical IDH mutations.
Gene:
KIT
Clinical Utility:
In GISTs, KIT mutations predict response to TKIs (imatinib, sunitinib), with secondary mutations associated with resistance. In metastatic melanoma cases, limited response to imatinib has been reported.
Gene:
NF1
Clinical Utility:
The nuclear factor I (NFI) is a family of transcription factors consisting of four distinct but closely related genes, NFIA, NFIB, NFIC and NFIX. Recent study results have shown that NFI family may play a critical role in the progression of various human tumors and have been identified as
key tumor suppressors and oncogenes for many cancers.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PDGFRA
Clinical Utility:
PDGFRA mutations predict response to TKIs (imatinib, sunitinib).
Gene:
SDHA
Clinical Utility:
Mutations of genes encoding the subunits of the succinate dehydrogenase (SDH) complex were described in KIT/PDGFRA wild-type GIST separately in different reports. The SDH complex is comprised of or modified by proteins encoded by SDHA, SDHB, SDHC, SDHD, and SDHAF2. In GIST, alterations in SDH have most commonly been reported in SDHB, but also have been found in SDHC, SDHD, and, recently, SDHA. Germline mutations in SDHB and SDHC have been identified in SDH-deficient GIST but appear to account for <15% of cases.
Gene:
SDHB
Clinical Utility:
Mutations of genes encoding the subunits of the succinate dehydrogenase (SDH) complex were described in KIT/PDGFRA wild-type GIST separately in different reports. The SDH complex is comprised of or modified by proteins encoded by SDHA, SDHB, SDHC, SDHD, and SDHAF2. In GIST, alterations in SDH have most commonly been reported in SDHB, but also have been found in SDHC, SDHD, and, recently, SDHA. Germline mutations in SDHB and SDHC have been identified in SDH-deficient GIST but appear to account for <15% of cases.
Gene:
SDHC
Clinical Utility:
Mutations of genes encoding the subunits of the succinate dehydrogenase (SDH) complex were described in KIT/PDGFRA wild-type GIST separately in different reports. The SDH complex is comprised of or modified by proteins encoded by SDHA, SDHB, SDHC, SDHD, and SDHAF2. In GIST, alterations in SDH have most commonly been reported in SDHB, but also have been found in SDHC, SDHD, and, recently, SDHA. Germline mutations in SDHB and SDHC have been identified in SDH-deficient GIST but appear to account for <15% of cases.
Gene:
SDHD
Clinical Utility:
Mutations of genes encoding the subunits of the succinate dehydrogenase (SDH) complex were described in KIT/PDGFRA wild-type GIST separately in different reports. The SDH complex is comprised of or modified by proteins encoded by SDHA, SDHB, SDHC, SDHD, and SDHAF2. In GIST, alterations in SDH have most commonly been reported in SDHB, but also have been found in SDHC, SDHD, and, recently, SDHA. Germline mutations in SDHB and SDHC have been identified in SDH-deficient GIST but appear to account for <15% of cases.
Gene:
AKT1
Clinical Utility:
AKT1 mutations may predict response to AKT1/mTOR inhibitors.
Gene:
AR
Clinical Utility:
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and ZBTB7A that recruits NCOR1 and NCOR2 to the androgen response elements/ARE on target genes, negatively regulating androgen receptor signaling and androgen-induced cell proliferation
Gene:
ATM
Clinical Utility:
A DNA-damage response gene that is commonly mutated in cancer. Germline mutations in this gene are thought to contribute to breast cancer susceptibility, and PARP inhibition is currently being studied for it’s potential in treating these patients. In lymphoid neoplasms, somatic mutations of ATM occur frequently in mantle cell lymphomas (MCL), chronic lymphoblastic leukemia (CLL) and T-cell prolymphocytic leukemia (TPLL).
Gene:
BRCA1
Clinical Utility:
In advance disease setting, mutations in homologous recombination repair genes such as BRCA1 and BRCA2 suggest candidacy for platinum chemotherapy and PARP inhibitor trials.
Gene:
BRCA2
Clinical Utility:
In advance disease setting, mutations in homologous recombination repair genes such as BRCA1 and BRCA2 suggest candidacy for platinum chemotherapy and PARP inhibitor trials.
Gene:
CDH1
Clinical Utility:
Involved in mechanisms regulating cell-cell adhesions, mobility and proliferation of epithelial cells. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis
Gene:
CHEK2
Clinical Utility:
Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors
Gene:
EGFR
Clinical Utility:
EGFR belongs to a family of four tyrosine kinases that encompasses ErbB1 (EGFR, HER1), ErbB2 (Her-2, Neu), ErbB3 (Her-3) and ErbB4 (Her-4). Amplifications and mutations in EGFR (HER1) were detected in 45–57% of GBM cases, indicating a causal role in the pathogenesis of GBM. EGFRs induce proliferation and have been implied in glioblastoma pathogenesis and resistance to treatment. EGFR is considered a potential therapeutic target for anti-EGFR therapy in triple-negative breast cancer (TNBC). Sensitizing EGFR mutations predict response to EGFR TKIs in NSCLC, including FDA-approved TKIs (erlotinib, gefitinib and afatinib), while other mutations predict resistance to first and second generation TKIs.
Gene:
EPCAM
Clinical Utility:
The Epithelial Cell Adhesion Molecule (EpCAM) has been shown to be strongly expressed in human breast cancer and cancer stem cells and its overexpression has been supposed to support tumor progression and metastasis. Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. EPCAM overexpression may be correlated with the development of bone metastasis and worse biochemical recurrence free-survival of
PCa.
Gene:
ERBB2
Clinical Utility:
Mutations in ERBB2 (HER2) are emerging targets associated with response to anti-HER2 antibody (trastuzumab) or TKI (afatinib) therapy in NSCLC. In breast cancer, ERBB2 over-expression or gene amplification is associated with response to established anti-HER2 targeted therapies. In CNS neoplasms, ErbB2/HER-2 mutation have been detected in 8–41% of glioblastoma cases.
Gene:
ESR1
Clinical Utility:
Activating mutations in ESR1 are associated with acquired resistance to endocrine therapy in hormone-dependent metastatic breast cancer.
Gene:
FANCA
Clinical Utility:
The FANCA gene is one of the genes in which mutations lead to Fanconi anaemia, a rare autosomal recessive disorder characterised by congenital abnormalities, bone marrow failure, and predisposition to malignancy. FANCA is also a potential breast and ovarian cancer susceptibility gene. Associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. Defects in genes involved in DNA damage repair (DDR) pathway are emerging as novel biomarkers and targets for new prostate cancer drug therapies.
Gene:
FGFR1
Clinical Utility:
Amplification of the FGFR1 gene predicts response to FGFR inhibition in several malignancies.
Gene:
FGFR2
Clinical Utility:
Alterations of FGFR2, including amplification, rearrangements and point mutations, predict response to FGFR inhibition in several malignancies.
Gene:
FOXA1
Clinical Utility:
The expression of FOXA1 is directly related to the expression of Androgen Receptor (AR). Despite that, FOXA1 is found as superior predicting marker of recurrences compared to AR in Estrogen Receptor postiive (ER+) Breast Cancer patients.
Gene:
KRAS
Clinical Utility:
KRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab). In NSCLC, KRAS mutations are associated with primary EGFR TKI resistance. In breast cancer, KRAS mRNA expression was found to be an independent prognostic factor. Prognostic role of KRAS mRNA expression was effective only in luminal A subtype breast cancer.
Gene:
MLH1
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. DNA mismatch repair (MMR) overexpression is common in prostate cancer and is linked to poor outcome as well as features indicating genetic instability. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors, whereas others have reported somatic hypermethylation of the MLH1 gene promoter, which is associated with MLH1 gene inactivation, in as many as 52% of colon tumors. Microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest
potential vulnerability to PD-1 inhibitors.
Gene:
MSH2
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer; Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
Gene:
MSH6
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. MSH6 is associated with an increased risk for breast cancer, and should be considered when ordering genetic testing for individuals who have a personal and/or family history of breast cancer.
Gene:
NBN
Clinical Utility:
Nibrin, encoded by the NBN gene, participates in DNA repair. Mutations in the NBN gene lead to Nijemen breakage syndrome (NBS), which may result in several types of diseases, particularly susceptibility to cancer, including breast cancer. Polymorphic variants and defective mutations occurring in the NBN gene increase the risk of breast cancer through the double-stranded break repair mechanism. NBN mutations/polymorphisms were also found in sporadic melanomas and basal cell carcinoma. In addition, NBS patients exhibited various skin abnormalities including abnormal pigmentation of the skin, sparse and thin hairs, and less frequently cutaneous non caseating granulomas porokeratosis, and depigmentation. Altogether these findings suggest a key function of NBN in skin homeostasis.
Gene:
MYC
Clinical Utility:
Activates the transcription of growth-related genes. Binds to the VEGFA promoter, promoting VEGFA production and subsequent sprouting angiogenesis. Regulator of somatic reprogramming, controls self-renewal of embryonic stem cells. Functions with TAF6L to activate target gene expression through RNA polymerase II pause release.
Gene:
NF1
Clinical Utility:
The nuclear factor I (NFI) is a family of transcription factors consisting of four distinct but closely related genes, NFIA, NFIB, NFIC and NFIX. Recent study results have shown that NFI family may play a critical role in the progression of various human tumors and have been identified as
key tumor suppressors and oncogenes for many cancers.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PALB2
Clinical Utility:
PALB2 (Partner and Localizer of Breast Cancer 2 (BRCA2)) plays an important role in maintaining genome integrity through its role in the Fanconi anemia (FA) and homologous recombination (HR) DNA repair pathways. PALB2 has emerged as a pivotal tumor suppressor protein associated to
hereditary cancer susceptibility to breast and pancreatic cancers. In advanced disease setting for prostate cancer, mutations in homologous recombination repair genes (eg, BRCA1, BRCA2, ATM, CHEK2, PALB2) suggest candidacy for platinum chemotherapy and PARP inhibitor trials.
Gene:
PIK3CA
Clinical Utility:
Mutations in PIK3CA may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
PMS2
Clinical Utility:
Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors. Additionally, lynch syndrome patients with PMS2 mutations may be at a higher risk of developing breast cancer. In prostate cancer, PMS2 plays a tumor suppresor role by enhancing apoptosis in prostate cancer cells.
Gene:
POLE
Clinical Utility:
POLE/POLD1 gene variants have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutational burden (TMB), an effective indicator for response prediction in immunotherapy.
Gene:
PTEN
Clinical Utility:
Mutations in PTEN may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
RAD51D
Clinical Utility:
Recent data indicate that men with prostate cancer may have germline mutations in 1 of 16 DNA repair genes including RAD51D (0.4%). Men with these inherited syndromes have an increased risk for prostate cancer. RAD51D germline mutations have been recently associated with ovarian and breast cancer.
Gene:
RB1
Clinical Utility:
Retinoblastoma 1 (RB1) is a gene that encodes a protein that is a negative regulator of the cell cycle as well as a tumor suppressor. Missense mutations, nonsense mutations, silent mutations, frameshift deletions and insertions, and in-frame deletions are observed in cancers such as
cancers of the fallopian tubes, cancers of the eye, and intestinal cancer. RB1 is altered in 4.03% of all cancers with lung adenocarcinoma, breast invasive ductal carcinoma, small cell lung carcinoma, bladder urothelial carcinoma, and colon adenocarcinoma having the greatest prevalence of alterations
Gene:
TBX3
Clinical Utility:
The T-box transcription factor 3 (TBX3), a member of this T-box factors family, is expressed in several tissues and plays critical roles in, among other structures, the heart, mammary gland and limbs and haploinsufficiency of the human TBX3 gene is the genetic basis for the autosomal
dominant disorder, ulnar-mammary syndrome. Overexpression of TBX3 on the other hand has been linked to several cancers including melanoma, breast, pancreatic, liver, lung, head and neck, ovarian, bladder carcinomas and a number of sarcoma subtypes. Furthermore, there is strong evidence that TBX3 promotes oncogenesis by impacting proliferation, tumour formation, metastasis as well as cell survival and drug resistance.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
TP53
Clinical Utility:
Somatic mutations in the TP53 gene are found in the majority of human cancers, and are generally associated with adverse prognostic characteristics in a number of tumor types.
Gene:
BAP1
Clinical Utility:
Mutation cause Tumor predisposition syndrome (TPDS). A condition characterized by predisposition to develop a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma, cutaneous melanoma, malignant mesothelioma on exposure to asbestos, lung adenocarcinoma and meningioma.
Gene:
BRAF
Clinical Utility:
Some mutations in BRAF predict response to RAF inhibitors in a variety of solid tumors. Therapies targeting BRAF V600-mutated melanoma (vemurafenib, dabrafenib, and trametinib) have been approved by the FDA. BRAF V600E is a negative prognostic marker in colorectal cancers, with resistance to anti-EGFR therapy in some clinical settings. In CNS neoplasms, BRAF V600E mutations are rarely found in adult gliomas with only 1% to 2 % mutated samples in glioblastomas and 2% to 5% in low grade adult gliomas. Even though a clear prognostic difference could not be established yet, BRAF V600E mutant glioblastomas have some distinct histopathological and molecular features. BRAF mutations are in most instances mutually exclusive to canonical IDH mutations.
Gene:
CDK4
Clinical Utility:
Loss of CDKN2A is common in lymphoid neoplasms, has prognostic implications in some alignancies, and presents a therapeutic target for CDK4/6 inhibitors.
Gene:
CDKN2A
Clinical Utility:
Loss of CDKN2A is common in lymphoid neoplasms, has prognostic implications in some malignancies, and presents a therapeutic target for CDK4/6 inhibitors.
Gene:
CTNNB1
Clinical Utility:
Activating CTNNB1 mutations may predict response to WNT inhibitors.
Gene:
EIF1AX
Clinical Utility:
The EIF1AX gene encodes for the eukaryotic translation initiation factor 1A, x-linked protein. This protein plays a role in the initiation of translation of mRNA to protein. In uveal melanoma, mutations in EIF1AX have been reported in the first two exons of the gene, which encode for
the unstructured N-terminal tail of the EIF1AX protein. EIF1AX mutations occur in approximately 17-24% of uveal melanomas and are usually not found in conjunction with SF3B1 or BAP1 mutations.
Gene:
GNA11
Clinical Utility:
Somatic mutations in either GNA11 or GNAQ genes are identified in majority of uveal melanoma cases.
Gene:
GNAQ
Clinical Utility:
Somatic mutations in either GNA11 or GNAQ genes are identified in the majority of uveal melanoma cases.
Gene:
GNAS
Clinical Utility:
Mutations are specific to uveal melanoma and other non-cutaneous melanomas, are not found in normal tissues, thus making them potential therapeutic targets.
Gene:
KIT
Clinical Utility:
In GISTs, KIT mutations predict response to TKIs (imatinib, sunitinib), with secondary mutations associated with resistance. In metastatic melanoma cases, limited response to imatinib has been reported.
Gene:
MAP2K1
Clinical Utility:
MAP2K1 mutations may confer resistance to BRAF and MEK inhibitors.
Gene:
MITF
Clinical Utility:
Plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1). Plays a critical role in the differentiation of various cell types, such as neural crest-derived melanocytes, mast cells, osteoclasts and optic
cup-derived retinal pigment epithelium
Gene:
NBN
Clinical Utility:
Nibrin, encoded by the NBN gene, participates in DNA repair. Mutations in the NBN gene lead to Nijemen breakage syndrome (NBS), which may result in several types of diseases, particularly susceptibility to cancer, including breast cancer. Polymorphic variants and defective mutations
occurring in the NBN gene increase the risk of breast cancer through the double-stranded break repair mechanism. NBN mutations/polymorphisms were also found in sporadic melanomas and basal cell carcinoma. In addition, NBS patients exhibited various skin abnormalities including abnormal pigmentation of the skin, sparse and thin hairs, and less frequently cutaneous non caseating granulomas porokeratosis, and depigmentation. Altogether these findings suggest a key function of NBN in skin homeostasis.
Gene:
NF1
Clinical Utility:
The nuclear factor I (NFI) is a family of transcription factors consisting of four distinct but closely related genes, NFIA, NFIB, NFIC and NFIX. Recent study results have shown that NFI family may play a critical role in the progression of various human tumors and have been identified as
key tumor suppressors and oncogenes for many cancers.
Gene:
NRAS
Clinical Utility:
Mutations and overexpression of the neuroblastoma RAS viral (v‐ras) oncogene homolog (NRAS) are found across multiple tumor types and are common in highly metastatic cancers such as tumors of unknown primary, melanomas, and sarcomas that display a striking propensity for lung metastasis. Clinical studies suggest that patients with NRAS‐mutant or amplified tumors suffer from more aggressive disease than patients with wild‐type NRAS alleles.NRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab), and may predict response to MEK inhibitors in metastatic melanoma.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PDGFRA
Clinical Utility:
PDGFRA mutations predict response to TKIs (imatinib, sunitinib).
Gene:
PIK3CA
Clinical Utility:
Mutations in PIK3CA may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
PTEN
Clinical Utility:
Mutations in PTEN may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
RB1
Clinical Utility:
Retinoblastoma 1 (RB1) is a gene that encodes a protein that is a negative regulator of the cell cycle as well as a tumor suppressor. Missense mutations, nonsense mutations, silent mutations, frameshift deletions and insertions, and in-frame deletions are observed in cancers such as
cancers of the fallopian tubes, cancers of the eye, and intestinal cancer. RB1 is altered in 4.03% of all cancers with lung adenocarcinoma, breast invasive ductal carcinoma, small cell lung carcinoma, bladder urothelial carcinoma, and colon adenocarcinoma having the greatest prevalence of alterations.
Gene:
SF3B1
Clinical Utility:
SF3B1 mutations were significantly associated with ER-positive disease, AKT1 mutations, and distinct copy number alterations. Additional profiling of hotspot mutations in a panel of special histological subtypes of breast cancer showed that 16% and 6% of papillary and mucinous
carcinomas of the breast harboured the SF3B1 K700E mutation. In uveal melanoma, SF3B1 mutations are generally associated with tumors having a favorable prognosis. In additon, SF3B1 R625 mutations in conjunction with GNAQ and GNA11 mutations are a genetic marker of malignancy in blue nevus-like melanocytic proliferations. In Chronic lymphocytic leukemia (CLL), SF3B1, a ubiquitously expressed splicing factor, has been found mutated in 5-17% of CLL cases, in which it is associated with a poor prognosis, reduced overall survival, and resistance to treatment with fludarabine.
Gene:
SMO
Clinical Utility:
The G protein-coupled receptor (GPCR) smoothened (SMO) is a key signaling component of the sonic hedgehog (Hh) pathway and a clinically validated target for cancer treatment. Curently FDA-approved SMO inhibitors are GDC-0449/Vismodegib and LDE225/Sonidegib.
Gene:
SRC
Clinical Utility:
SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) is an important driver of YAP/TAZ activity in human breast cancer and melanoma cells. SRC activation increased YAP/TAZ activity and the expression of YAP/TAZ-regulated genes.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
TP53
Clinical Utility:
Somatic mutations in the TP53 gene are found in the majority of human cancers, and are generally associated with adverse prognostic characteristics in a number of tumor types.

OnkoSight AdvancedTM Melanoma Panel (25 genes), TMB and MSI
Test Code: TH59-9

BAP1BRAFCDK4CDKN2ACTNNB1EIF1AXGNA11GNAQGNAS
KITMAP2K1MITFNBNNF1NRASNTRK1PDGFRAPIK3CA
PTENRB1SF3B1SMOSRCTERTTP53
Gene:
BRAF
Clinical Utility:
Some mutations in BRAF predict response to RAF inhibitors in a variety of solid tumors. Therapies targeting BRAF V600-mutated melanoma (vemurafenib, dabrafenib, and trametinib) have been approved by the FDA. BRAF V600E is a negative prognostic marker in colorectal cancers, with resistance to anti-EGFR therapy in some clinical settings. In CNS neoplasms, BRAF V600E mutations are rarely found in adult gliomas with only 1% to 2 % mutated samples in glioblastomas and 2% to 5% in low grade adult gliomas. Even though a clear prognostic difference could not be established yet, BRAF V600E mutant glioblastomas have some distinct histopathological and molecular features. BRAF mutations are in most
instances mutually exclusive to canonical IDH mutations.
Gene:
KIT
Clinical Utility:
In GISTs, KIT mutations predict response to TKIs (imatinib, sunitinib), with secondary mutations associated with resistance. In metastatic melanoma cases, limited response to imatinib has been reported.
Gene:
NF1
Clinical Utility:
The nuclear factor I (NFI) is a family of transcription factors consisting of four distinct but closely related genes, NFIA, NFIB, NFIC and NFIX. Recent study results have shown that NFI family may play a critical role in the progression of various human tumors and have been identified as key tumor suppressors and oncogenes for many cancers.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PDGFRA
Clinical Utility:
PDGFRA mutations predict response to TKIs (imatinib, sunitinib).
Gene:
SDHA
Clinical Utility:
Mutations of genes encoding the subunits of the succinate dehydrogenase (SDH) complex were described in KIT/PDGFRA wild-type GIST separately in different reports. The SDH complex is comprised of or modified by proteins encoded by SDHA, SDHB, SDHC, SDHD, and SDHAF2. In GIST, alterations in SDH have most commonly been reported in SDHB, but also have been found in SDHC, SDHD, and, recently, SDHA. Germline mutations in SDHB and SDHC have been identified in SDH-deficient GIST but appear to account for <15% of cases.
Gene:
SDHB
Clinical Utility:
Mutations of genes encoding the subunits of the succinate dehydrogenase (SDH) complex were described in KIT/PDGFRA wild-type GIST separately in different reports. The SDH complex is comprised of or modified by proteins encoded by SDHA, SDHB, SDHC, SDHD, and SDHAF2. In GIST, alterations in SDH have most commonly been reported in SDHB, but also have been found in SDHC, SDHD, and, recently, SDHA. Germline mutations in SDHB and SDHC have been identified in SDH-deficient GIST but appear to account for <15% of cases.
Gene:
SDHC
Clinical Utility:
Mutations of genes encoding the subunits of the succinate dehydrogenase (SDH) complex were described in KIT/PDGFRA wild-type GIST separately in different reports. The SDH complex is comprised of or modified by proteins encoded by SDHA, SDHB, SDHC, SDHD, and SDHAF2. In GIST, alterations in SDH have most commonly been reported in SDHB, but also have been found in SDHC, SDHD, and, recently, SDHA. Germline mutations in SDHB and SDHC have been identified in SDH-deficient GIST but appear to account for <15% of cases.
Gene:
SDHD
Clinical Utility:
Mutations of genes encoding the subunits of the succinate dehydrogenase (SDH) complex were described in KIT/PDGFRA wild-type GIST separately in different reports. The SDH complex is comprised of or modified by proteins encoded by SDHA, SDHB, SDHC, SDHD, and SDHAF2. In GIST, alterations in SDH have most commonly been reported in SDHB, but also have been found in SDHC, SDHD, and, recently, SDHA. Germline mutations in SDHB and SDHC have been identified in SDH-deficient GIST but appear to account for <15% of cases.
Gene:
AKT1
Clinical Utility:
AKT1 mutations may predict response to AKT1/mTOR inhibitors.
Gene:
AR
Clinical Utility:
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and ZBTB7A that recruits NCOR1 and NCOR2 to the androgen response elements/ARE on target genes, negatively regulating androgen receptor signaling and androgen-induced cell proliferation.
Gene:
ATM
Clinical Utility:
A DNA-damage response gene that is commonly mutated in cancer. Germline mutations in this gene are thought to contribute to breast cancer susceptibility, and PARP inhibition is currently being studied for it’s potential in treating these patients. In lymphoid neoplasms, somatic mutations of ATM occur frequently in mantle cell lymphomas (MCL), chronic lymphoblastic leukemia (CLL) and T-cell prolymphocytic leukemia (TPLL).
Gene:
BRCA1
Clinical Utility:
In advance disease setting, mutations in homologous recombination repair genes such as BRCA1 and BRCA2 suggest candidacy for platinum chemotherapy and PARP inhibitor trials.
Gene:
BRCA2
Clinical Utility:
In advance disease setting, mutations in homologous recombination repair genes such as BRCA1 and BRCA2 suggest candidacy for platinum chemotherapy and PARP inhibitor trials.
Gene:
CDH1
Clinical Utility:
Involved in mechanisms regulating cell-cell adhesions, mobility and proliferation of epithelial cells. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis.
Gene:
CHEK2
Clinical Utility:
Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors.
Gene:
EGFR
Clinical Utility:
EGFR belongs to a family of four tyrosine kinases that encompasses ErbB1 (EGFR, HER1), ErbB2 (Her-2, Neu), ErbB3 (Her-3) and ErbB4 (Her-4). Amplifications and mutations in EGFR (HER1) were detected in 45–57% of GBM cases, indicating a causal role in the pathogenesis of GBM. EGFRs induce proliferation and have been implied in glioblastoma pathogenesis and resistance to treatment. EGFR is considered a potential therapeutic target for anti-EGFR therapy in triple-negative breast cancer (TNBC). Sensitizing EGFR mutations predict response to EGFR TKIs in NSCLC, including FDA-approved TKIs (erlotinib, gefitinib and afatinib), while other mutations predict resistance to first and second generation TKIs.
Gene:
EPCAM
Clinical Utility:
The Epithelial Cell Adhesion Molecule (EpCAM) has been shown to be strongly expressed in human breast cancer and cancer stem cells and its overexpression has been supposed to support tumor progression and metastasis. Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. EPCAM overexpression may be correlated with the development of bone metastasis and worse biochemical recurrence free-survival of PCa.
Gene:
ERBB2
Clinical Utility:
Mutations in ERBB2 (HER2) are emerging targets associated with response to anti-HER2 antibody (trastuzumab) or TKI (afatinib) therapy in NSCLC. In breast cancer, ERBB2 over-expression or gene amplification is associated with response to established anti-HER2 targeted therapies. In CNS neoplasms, ErbB2/HER-2 mutation have been detected in 8–41% of glioblastoma cases.
Gene:
ESR1
Clinical Utility:
Activating mutations in ESR1 are associated with acquired resistance to endocrine therapy in hormone-dependent metastatic breast cancer.
Gene:
FANCA
Clinical Utility:
The FANCA gene is one of the genes in which mutations lead to Fanconi anaemia, a rare autosomal recessive disorder characterised by congenital abnormalities, bone marrow failure, and predisposition to malignancy. FANCA is also a potential breast and ovarian cancer susceptibility gene. Associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. Defects in genes involved in DNA damage repair (DDR) pathway are emerging as novel biomarkers and targets for new prostate cancer drug therapies.
Gene:
FGFR1
Clinical Utility:
Amplification of the FGFR1 gene predicts response to FGFR inhibition in several malignancies.
Gene:
FGFR2
Clinical Utility:
Alterations of FGFR2, including amplification, rearrangements and point mutations, predict response to FGFR inhibition in several malignancies.
Gene:
FOXA1
Clinical Utility:
The expression of FOXA1 is directly related to the expression of Androgen Receptor (AR). Despite that, FOXA1 is found as superior predicting marker of recurrences compared to AR in Estrogen Receptor postiive (ER+) Breast Cancer patients.
Gene:
KRAS
Clinical Utility:
KRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab). In NSCLC, KRAS mutations are associated with primary EGFR TKI resistance. In breast cancer, KRAS mRNA expression was found to be an independent prognostic factor. Prognostic role of KRAS mRNA expression was effective only in luminal A subtype breast cancer.
Gene:
MLH1
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. DNA mismatch repair (MMR) overexpression is common in prostate cancer and is linked to poor outcome as well as features indicating genetic instability. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors, whereas others have reported somatic hypermethylation of the MLH1 gene promoter, which is associated with MLH1 gene inactivation, in as many as 52% of colon tumors. Microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest potential vulnerability to PD-1 inhibitors.
Gene:
MSH2
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer; Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
Gene:
MSH6
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. MSH6 is associated with an increased risk for breast cancer, and should be considered when ordering genetic testing for individuals who have a personal and/or family history of breast cancer.
Gene:
NBN
Clinical Utility:
Nibrin, encoded by the NBN gene, participates in DNA repair. Mutations in the NBN gene lead to Nijemen breakage syndrome (NBS), which may result in several types of diseases, particularly susceptibility to cancer, including breast cancer. Polymorphic variants and defective mutations occurring in the NBN gene increase the risk of breast cancer through the double-stranded break repair mechanism. NBN  mutations/polymorphisms were also found in sporadic melanomas and basal cell carcinoma. In addition, NBS patients exhibited various skin abnormalities including abnormal pigmentation of the skin, sparse and thin hairs, and less frequently cutaneous non caseating granulomas porokeratosis, and depigmentation. Altogether these findings suggest a key function of NBN in skin homeostasis.
Gene:
MYC
Clinical Utility:
Activates the transcription of growth-related genes. Binds to the VEGFA promoter, promoting VEGFA production and subsequent sprouting angiogenesis. Regulator of somatic reprogramming, controls self-renewal of embryonic stem cells. Functions with TAF6L to activate target gene expression through RNA polymerase II pause release.
Gene:
NF1
Clinical Utility:
The nuclear factor I (NFI) is a family of transcription factors consisting of four distinct but closely related genes, NFIA, NFIB, NFIC and NFIX. Recent study results have shown that NFI family may play a critical role in the progression of various human tumors and have been identified as key tumor suppressors and oncogenes for many cancers.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PALB2
Clinical Utility:
PALB2 (Partner and Localizer of Breast Cancer 2 (BRCA2)) plays an important role in maintaining genome integrity through its role in the Fanconi anemia (FA) and homologous recombination (HR) DNA repair pathways. PALB2 has emerged as a pivotal tumor suppressor protein associated to hereditary cancer susceptibility to breast and pancreatic cancers. In advanced disease setting for prostate cancer, mutations in homologous recombination repair genes (eg, BRCA1, BRCA2, ATM, CHEK2, PALB2) suggest candidacy for platinum chemotherapy and PARP inhibitor trials.
Gene:
PIK3CA
Clinical Utility:
Mutations in PIK3CA may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
PMS2
Clinical Utility:
Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors. Additionally, lynch syndrome patients with PMS2 mutations may be at a higher risk of developing breast cancer. In prostate cancer, PMS2 plays a tumor suppresor role by enhancing apoptosis in prostate cancer cells.
Gene:
POLE
Clinical Utility:
POLE/POLD1 gene variants have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutational burden (TMB), an effective indicator for response prediction in immunotherapy.
Gene:
PTEN
Clinical Utility:
Mutations in PTEN may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
RAD51D
Clinical Utility:
Recent data indicate that men with prostate cancer may have germline mutations in 1 of 16 DNA repair genes including RAD51D (0.4%). Men with these inherited syndromes have an increased risk for prostate cancer. RAD51D germline mutations have been recently associated with ovarian and breast cancer.
Gene:
RB1
Clinical Utility:
Retinoblastoma 1 (RB1) is a gene that encodes a protein that is a negative regulator of the cell cycle as well as a tumor suppressor. Missense mutations, nonsense mutations, silent mutations, frameshift deletions and insertions, and in-frame deletions are observed in cancers such as cancers of the fallopian tubes, cancers of the eye, and intestinal cancer. RB1 is altered in 4.03% of all cancers with lung adenocarcinoma, breast invasive ductal carcinoma, small cell lung carcinoma, bladder urothelial carcinoma, and colon adenocarcinoma having the greatest prevalence of alterations.
Gene:
TBX3
Clinical Utility:
The T-box transcription factor 3 (TBX3), a member of this T-box factors family, is expressed in several tissues and plays critical roles in, among other structures, the heart, mammary gland and limbs and haploinsufficiency of the human TBX3 gene is the genetic basis for the autosomal dominant disorder, ulnar-mammary syndrome. Overexpression of TBX3 on the other hand has been linked to several cancers including melanoma, breast, pancreatic, liver, lung, head and neck, ovarian, bladder carcinomas and a number of sarcoma subtypes. Furthermore, there is strong evidence that TBX3 promotes oncogenesis by impacting proliferation, tumour formation, metastasis as well as cell survival and drug resistance.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
TP53
Clinical Utility:
Somatic mutations in the TP53 gene are found in the majority of human cancers, and are generally associated with adverse prognostic characteristics in a number of tumor types.
Gene:
BAP1
Clinical Utility:
Mutation cause Tumor predisposition syndrome (TPDS). A condition characterized by predisposition to develop a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma, cutaneous melanoma, malignant mesothelioma on exposure to asbestos, lung adenocarcinoma and meningioma.
Gene:
BRAF
Clinical Utility:
Some mutations in BRAF predict response to RAF inhibitors in a variety of solid tumors. Therapies targeting BRAF V600-mutated melanoma (vemurafenib, dabrafenib, and trametinib) have been approved by the FDA. BRAF V600E is a negative prognostic marker in colorectal cancers, with resistance to anti-EGFR therapy in some clinical settings. In CNS neoplasms, BRAF V600E mutations are rarely found in adult gliomas with only 1% to 2 % mutated samples in glioblastomas and 2% to 5% in low grade adult gliomas. Even though a clear prognostic difference could not be established yet, BRAF V600E mutant glioblastomas have some distinct histopathological and molecular features. BRAF mutations are in most
instances mutually exclusive to canonical IDH mutations.
Gene:
CDK4
Clinical Utility:
Loss of CDKN2A is common in lymphoid neoplasms, has prognostic implications in some malignancies, and presents a therapeutic target for CDK4/6 inhibitors.
Gene:
CDKN2A
Clinical Utility:
Loss of CDKN2A is common in lymphoid neoplasms, has prognostic implications in some malignancies, and presents a therapeutic target for CDK4/6 inhibitors.
Gene:
CTNNB1
Clinical Utility:
Activating CTNNB1 mutations may predict response to WNT inhibitors.
Gene:
EIF1AX
Clinical Utility:
The EIF1AX gene encodes for the eukaryotic translation initiation factor 1A, x-linked protein. This protein plays a role in the initiation of translation of mRNA to protein. In uveal melanoma, mutations in EIF1AX have been reported in the first two exons of the gene, which encode for the unstructured N-terminal tail of the EIF1AX protein. EIF1AX mutations occur in approximately 17-24% of uveal melanomas and are usually not found in conjunction with SF3B1 or BAP1 mutations.
Gene:
GNA11
Clinical Utility:
Somatic mutations in either GNA11 or GNAQ genes are identified in majority of uveal melanoma cases.
Gene:
GNAQ
Clinical Utility:
Somatic mutations in either GNA11 or GNAQ genes are identified in the majority of uveal melanoma cases.
Gene:
GNAS
Clinical Utility:
Mutations are specific to uveal melanoma and other non-cutaneous melanomas, are not found in normal tissues, thus making them potential therapeutic targets.
Gene:
KIT
Clinical Utility:
In GISTs, KIT mutations predict response to TKIs (imatinib, sunitinib), with secondary mutations associated with resistance. In metastatic melanoma cases, limited response to imatinib has been reported.
Gene:
MAP2K1
Clinical Utility:
MAP2K1 mutations may confer resistance to BRAF and MEK inhibitors.
Gene:
MITF
Clinical Utility:
Plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1). Plays a critical role in the differentiation of various cell types, such as neural crest-derived melanocytes, mast cells, osteoclasts and optic cup-derived retinal pigment epithelium
Gene:
NBN
Clinical Utility:
Nibrin, encoded by the NBN gene, participates in DNA repair. Mutations in the NBN gene lead to Nijemen breakage syndrome (NBS), which may result in several types of diseases, particularly susceptibility to cancer, including breast cancer. Polymorphic variants and defective mutations occurring in the NBN gene increase the risk of breast cancer through the double-stranded break repair mechanism. NBN mutations/polymorphisms were also found in sporadic melanomas and basal cell carcinoma. In addition, NBS patients exhibited various skin abnormalities including abnormal pigmentation of the skin, sparse and thin hairs, and less frequently cutaneous non caseating granulomas porokeratosis, and depigmentation. Altogether these findings suggest a key function of NBN in skin homeostasis.
Gene:
NF1
Clinical Utility:
The nuclear factor I (NFI) is a family of transcription factors consisting of four distinct but closely related genes, NFIA, NFIB, NFIC and NFIX. Recent study results have shown that NFI family may play a critical role in the progression of various human tumors and have been identified as key tumor suppressors and oncogenes for many cancers.
Gene:
NRAS
Clinical Utility:
Mutations and overexpression of the neuroblastoma RAS viral (v‐ras) oncogene homolog (NRAS) are found across multiple tumor types and are common in highly metastatic cancers such as tumors of unknown primary, melanomas, and sarcomas that display a striking propensity for lung metastasis. Clinical studies suggest that patients with NRAS‐mutant or amplified tumors suffer from more aggressive disease than patients with wild‐type NRAS alleles.NRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab), and may predict response to MEK inhibitors in metastatic melanoma.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PDGFRA
Clinical Utility:
PDGFRA mutations predict response to TKIs (imatinib, sunitinib).
Gene:
PIK3CA
Clinical Utility:
Mutations in PIK3CA may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
PTEN
Clinical Utility:
Mutations in PTEN may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
RB1
Clinical Utility:
Retinoblastoma 1 (RB1) is a gene that encodes a protein that is a negative regulator of the cell cycle as well as a tumor suppressor. Missense mutations, nonsense mutations, silent mutations, frameshift deletions and insertions, and in-frame deletions are observed in cancers such as cancers of the fallopian tubes, cancers of the eye, and intestinal cancer. RB1 is altered in 4.03% of all cancers with lung adenocarcinoma, breast invasive ductal carcinoma, small cell lung carcinoma, bladder urothelial carcinoma, and colon adenocarcinoma having the greatest prevalence of alterations.
Gene:
SF3B1
Clinical Utility:
SF3B1 mutations were significantly associated with ER-positive disease, AKT1 mutations, and distinct copy number alterations. Additional profiling of hotspot mutations in a panel of special histological subtypes of breast cancer showed that 16% and 6% of papillary and mucinous carcinomas of the breast harboured the SF3B1 K700E mutation. In uveal melanoma, SF3B1 mutations are generally associated with tumors having a favorable prognosis. In additon, SF3B1 R625 mutations in conjunction with GNAQ and GNA11 mutations are a genetic marker of malignancy in blue nevus-like melanocytic proliferations. In Chronic lymphocytic leukemia (CLL), SF3B1, a ubiquitously expressed splicing factor, has been found mutated in 5-17% of CLL cases, in which it is associated with a poor prognosis, reduced overall survival, and resistance to treatment with fludarabine.
Gene:
SMO
Clinical Utility:
The G protein-coupled receptor (GPCR) smoothened (SMO) is a key signaling component of the sonic hedgehog (Hh) pathway and a clinically validated target for cancer treatment. Curently FDA-approved SMO inhibitors are GDC-0449/Vismodegib and LDE225/Sonidegib.
Gene:
SRC
Clinical Utility:
SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) is an important driver of YAP/TAZ activity in human breast cancer and melanoma cells. SRC activation increased YAP/TAZ activity and the expression of YAP/TAZ-regulated genes.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
TP53
Clinical Utility:
Somatic mutations in the TP53 gene are found in the majority of human cancers, and are generally associated with adverse prognostic characteristics in a number of tumor types.

OnkoSight AdvancedTM Lung Cancer Panel (18 genes), TMB and MSI
Test Code: TH49-0

ATK1ALKBRAFDDR2EGFRERBB2FGFR1KRASMAP2K1
METNRASNTRK1PIK3CAPOLD1POLESTK11TERTTP53
Gene:
AKT1
Clinical Utility:
AKT1 mutations may predict response to AKT1/mTOR inhibitors.
Gene:
ALK
Clinical Utility:
Rearrangements of the ALK gene in NSCLC predict therapeutic response to ALK kinase inhibitors, including FDA-approved crizotinib and ceritinib, and resistance to EGFR inhibitors. Secondary ALK mutations and gene amplifications are associated with acquired resistance to crizotinib and variable response to second-generation ALK inhibitors.
Gene:
BRAF
Clinical Utility:
Some mutations in BRAF predict response to RAF inhibitors in a variety of solid tumors. Therapies targeting BRAF V600-mutated melanoma (vemurafenib, dabrafenib, and trametinib) have been approved by the FDA. BRAF V600E is a negative prognostic marker in colorectal cancers, with resistance to anti-EGFR therapy in some clinical settings. In CNS neoplasms, BRAF V600E mutations are rarely found in adult gliomas
with only 1% to 2 % mutated samples in glioblastomas and 2% to 5% in low grade adult gliomas. Even though a clear prognostic difference could not be established yet, BRAF V600E mutant glioblastomas have some distinct histopathological and molecular features. BRAF mutations are in most instances mutually exclusive to canonical IDH mutations.
Gene:
DDR2
Clinical Utility:
In squamous cell lung cancer, DDR2 mutations may predict response to dasatinib and other receptor tyrosine kinase inhibitors.
Gene:
EGFR
Clinical Utility:
EGFR belongs to a family of four tyrosine kinases that encompasses ErbB1 (EGFR, HER1), ErbB2 (Her-2, Neu), ErbB3 (Her-3) and ErbB4 (Her-4). Amplifications and mutations in EGFR (HER1) were detected in 45–57% of GBM cases, indicating a causal role in the pathogenesis of GBM. EGFRs induce proliferation and have been implied in glioblastoma pathogenesis and resistance to treatment. EGFR is considered a potential therapeutic target for anti-EGFR therapy in triple-negative breast cancer (TNBC). Sensitizing EGFR mutations predict response to EGFR TKIs in NSCLC, including FDA-approved TKIs (erlotinib, gefitinib and afatinib), while other mutations predict resistance to first and second generation TKIs.
Gene:
ERBB2
Clinical Utility:
Mutations in ERBB2 (HER2) are emerging targets associated with response to anti-HER2 antibody (trastuzumab) or TKI (afatinib) therapy in NSCLC. In breast cancer, ERBB2 over-expression or gene amplification is associated with response to established anti-HER2 targeted therapies. In CNS neoplasms, ErbB2/HER-2 mutation have been detected in 8–41% of glioblastoma cases.
Gene:
FGFR1
Clinical Utility:
Amplification of the FGFR1 gene predicts response to FGFR inhibition in several malignancies.
Gene:
KRAS
Clinical Utility:
KRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab). In NSCLC, KRAS mutations are associated with primary EGFR TKI resistance. In breast cancer, KRAS mRNA expression was found to be an independent prognostic factor. Prognostic role of KRAS mRNA expression was effective only in luminal A subtype breast cancer.
Gene:
MAP2K1
Clinical Utility:
MAP2K1 mutations may confer resistance to BRAF and MEK inhibitors.
Gene:
MET
Clinical Utility:
MET alterations in solid tumors, including amplification and mutations, may predict response to MET inhibitors. MET amplification has been associated with acquired resistance to anti-EGFR TKIs in lung cancer.
Gene:
NRAS
Clinical Utility:
Mutations and overexpression of the neuroblastoma RAS viral (v‐ras) oncogene homolog (NRAS) are found across multiple tumor types and are common in highly metastatic cancers such as tumors of unknown primary, melanomas, and sarcomas that display a striking propensity for lung metastasis. Clinical studies suggest that patients with NRAS‐mutant or amplified tumors suffer from more aggressive disease than patients with wild‐type NRAS alleles.NRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab), and may predict response to MEK inhibitors in metastatic melanoma.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PIK3CA
Clinical Utility:
Mutations in PIK3CA may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
POLD1
Clinical Utility:
POLE/POLD1 gene variants have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutational burden (TMB), an effective indicator for response prediction in immunotherapy.
Gene:
POLE
Clinical Utility:
POLE/POLD1 gene variants have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutational burden (TMB), an effective indicator for response prediction in immunotherapy.
Gene:
STK11
Clinical Utility:
STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. In one clinical study, it was found that STK11/LKB1 alterations is the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Mutations in this gene have been associated with Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by the growth of polyps in the gastrointestinal tract, pigmented macules on the skin and mouth, and other neoplasms. Several published reports have demonstrated the PJS predisposes carriers to cancers of the gastrointestinal tract, as well as susceptibility to a variety of tumors.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
TP53
Clinical Utility:
Somatic mutations in the TP53 gene are found in the majority of human cancers, and are generally associated with adverse prognostic characteristics in a number of tumor types.
Gene:
AR
Clinical Utility:
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and ZBTB7A that recruits NCOR1 and NCOR2 to the androgen response elements/ARE on target genes, negatively regulating androgen receptor signaling and androgen-induced cell proliferation
Gene:
ATM
Clinical Utility:
A DNA-damage response gene that is commonly mutated in cancer. Germline mutations in this gene are thought to contribute to breast cancer susceptibility, and PARP inhibition is currently being studied for it’s potential in treating these patients. In lymphoid neoplasms, somatic mutations of ATM occur frequently in mantle cell lymphomas (MCL), chronic lymphoblastic leukemia (CLL) and T-cell prolymphocytic
leukemia (TPLL).
Gene:
BRCA1
Clinical Utility:
In advance disease setting, mutations in homologous recombination repair genes such as BRCA1 and BRCA2 suggest candidacy for platinum chemotherapy and PARP inhibitor trials.
Gene:
BRCA2
Clinical Utility:
In advance disease setting, mutations in homologous recombination repair genes such as BRCA1 and BRCA2 suggest candidacy for platinum chemotherapy and PARP inhibitor trials.
Gene:
CHEK2
Clinical Utility:
Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors
Gene:
EPCAM
Clinical Utility:
The Epithelial Cell Adhesion Molecule (EpCAM) has been shown to be strongly expressed in human breast cancer and cancer stem cells and its overexpression has been supposed to support tumor progression and metastasis. Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. EPCAM overexpression may be correlated with the development of bone metastasis and worse biochemical recurrence free-survival of PCa.
Gene:
FANCA
Clinical Utility:
The FANCA gene is one of the genes in which mutations lead to Fanconi anaemia, a rare autosomal recessive disorder characterised by congenital abnormalities, bone marrow failure, and predisposition to malignancy. FANCA is also a potential breast and ovarian cancer susceptibility
gene. Associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. Defects in genes involved in DNA damage repair (DDR) pathway are emerging as novel biomarkers and targets for new prostate cancer drug therapies.
Gene:
HOXB13
Clinical Utility:
HOXB13, a member of the homeobox proteins family, is a key regulator of the epithelial differentiation in the prostate gland. HOXB13 is overexpressed during malignant progression of the prostatic tissue and suspected to contribute in the pathogenesis of the prostate gland. HOXB13 together with BRCA2 mutations have been consistently shown to increase prostate cancer risk, and are more commonly observed among patients diagnosed with early-onset disease.
Gene:
MLH1
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. DNA mismatch repair (MMR) overexpression is common in prostate cancer and is linked to poor outcome as well as features indicating genetic instability. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors, whereas others have
reported somatic hypermethylation of the MLH1 gene promoter, which is associated with MLH1 gene inactivation, in as many as 52% of colon tumors. Microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest potential vulnerability to PD-1 inhibitors.
Gene:
MSH2
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2-to 5.8-fold increase in risk for prostate cancer; Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Loss of MSH2 protein is correlated  with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most
common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
Gene:
MSH6
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. MSH6 is associated with an increased risk for breast cancer, and should be considered when ordering genetic testing for individuals who have a personal and/or family history of breast cancer.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PALB2
Clinical Utility:
PALB2 (Partner and Localizer of Breast Cancer 2 (BRCA2)) plays an important role in maintaining genome integrity through its role in the Fanconi anemia (FA) and homologous recombination (HR) DNA repair pathways. PALB2 has emerged as a pivotal tumor suppressor protein associated to hereditary cancer susceptibility to breast and pancreatic cancers. In advanced disease setting for prostate cancer, mutations in homologous recombination repair genes (eg, BRCA1, BRCA2, ATM, CHEK2, PALB2) suggest candidacy for platinum chemotherapy and PARP inhibitor trials.
Gene:
PMS2
Clinical Utility:
Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors. Additionally, lynch syndrome patients with PMS2 mutations may be at a higher risk of developing breast cancer. In prostate cancer, PMS2 plays a tumor suppresor role by enhancing apoptosis in prostate cancer cells.
Gene:
PTEN
Clinical Utility:
Mutations in PTEN may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
RAD51D
Clinical Utility:
Recent data indicate that men with prostate cancer may have germline mutations in 1 of 16 DNA repair genes including RAD51D (0.4%). Men with these inherited syndromes have an increased risk for prostate cancer. RAD51D germline mutations have been recently associated with ovarian and breast cancer.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival
compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
AKT1
Clinical Utility:
AKT1 mutations may predict response to AKT1/mTOR inhibitors.
Gene:
ALK
Clinical Utility:
Rearrangements of the ALK gene in NSCLC predict therapeutic response to ALK kinase inhibitors, including FDA-approved crizotinib and ceritinib, and resistance to EGFR inhibitors. Secondary ALK mutations and gene amplifications are associated with acquired resistance to crizotinib and variable response to second-generation ALK inhibitors.
Gene:
APC
Clinical Utility:
Tumor suppressor. Promotes rapid degradation of CTNNB1 and participates in Wnt signaling as a negative regulator. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells.
Gene:
ARID1A
Clinical Utility:
ARID1A is mutated in over 50% of ovarian clear cell carcinomas and 30% of ovarian endometrioid carcinomas. ARID1A mutation is a known genetic driver of ovarian cancer. Over 90% of the ARID1A mutations observed in ovarian cancer are frame-shift or nonsense mutations that result in loss of ARID1A protein expression.Loss of ARID1A correlates with late-stage disease and predicts early recurrence of ovarian clear cell carcinoma.
Gene:
ATM
Clinical Utility:
A DNA-damage response gene that is commonly mutated in cancer. Germline mutations in this gene are thought to contribute to breast cancer susceptibility, and PARP inhibition is currently being studied for it’s potential in treating these patients. In lymphoid neoplasms, somatic mutations of ATM occur frequently in mantle cell lymphomas (MCL), chronic lymphoblastic leukemia (CLL) and T-cell prolymphocytic leukemia (TPLL).
Gene:
BRAF
Clinical Utility:
Some mutations in BRAF predict response to RAF inhibitors in a variety of solid tumors. Therapies targeting BRAF V600-mutated melanoma (vemurafenib, dabrafenib, and trametinib) have been approved by the FDA. BRAF V600E is a negative prognostic marker in colorectal cancers, with resistance to anti-EGFR therapy in some clinical settings. In CNS neoplasms, BRAF V600E mutations are rarely found in adult gliomas
with only 1% to 2 % mutated samples in glioblastomas and 2% to 5% in low grade adult gliomas. Even though a clear prognostic difference could not be established yet, BRAF V600E mutant glioblastomas have some distinct histopathological and molecular features. BRAF mutations are in most instances mutually exclusive to canonical IDH mutations.
Gene:
CDH1
Clinical Utility:
Involved in mechanisms regulating cell-cell adhesions, mobility and proliferation of epithelial cells. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis
Gene:
CDKN2A
Clinical Utility:
Loss of CDKN2A is common in lymphoid neoplasms, has prognostic implications in some malignancies, and presents a therapeutic target for CDK4/6 inhibitors.
Gene:
CTNNB1
Clinical Utility:
Activating CTNNB1 mutations may predict response to WNT inhibitors.
Gene:
EGFR
Clinical Utility:
EGFR belongs to a family of four tyrosine kinases that encompasses ErbB1 (EGFR, HER1), ErbB2 (Her-2, Neu), ErbB3 (Her-3) and ErbB4 (Her-4). Amplifications and mutations in EGFR (HER1) were detected in 45–57% of GBM cases, indicating a causal role in the pathogenesis of GBM. EGFRs induce proliferation and have been implied in glioblastoma pathogenesis and resistance to treatment. EGFR is considered a potential therapeutic target for anti-EGFR therapy in triple-negative breast cancer (TNBC). Sensitizing EGFR mutations predict response to EGFR TKIs in NSCLC, including FDA-approved TKIs (erlotinib, gefitinib and afatinib), while other mutations predict resistance to first and second generation TKIs.
Gene:
EPCAM
Clinical Utility:
The Epithelial Cell Adhesion Molecule (EpCAM) has been shown to be strongly expressed in human breast cancer and cancer stem cells and its overexpression has been supposed to support tumor progression and metastasis. Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. EPCAM overexpression may be correlated with the
development of bone metastasis and worse biochemical recurrence free-survival of PCa.
Gene:
ERBB2
Clinical Utility:
Mutations in ERBB2 (HER2) are emerging targets associated with response to anti-HER2 antibody (trastuzumab) or TKI (afatinib) therapy in NSCLC. In breast cancer, ERBB2 over-expression or gene amplification is associated with response to established anti-HER2 targeted therapies. In CNS neoplasms, ErbB2/HER-2 mutation have been detected in 8–41% of glioblastoma cases.
Gene:
ERBB4
Clinical Utility:
The ErbB signalling network plays a crucial role in the growth and progression of several cancers, including colorectal cancer (CRC), and includes potentially drug-targetable genes. Oncogenic activation of the ErbB pathway by mutations and focal amplifications have emerged recently as an important predictive marker of the prognosis of CRC patients.
Gene:
FBXW7
Clinical Utility:
Mutations in the FBXW7 tumor suppressor have been observed in some hematological malignancies, including CLL and T-ALL.
Gene:
FGFR1
Clinical Utility:
Amplification of the FGFR1 gene predicts response to FGFR inhibition in several malignancies.
Gene:
FGFR2
Clinical Utility:
Alterations of FGFR2, including amplification, rearrangements and point mutations, predict response to FGFR inhibition in several malignancies.
Gene:
FGFR3
Clinical Utility:
Alterations of FGFR3, including amplification, rearrangements and point mutations, predict response to FGFR inhibition in several malignancies.
Gene:
GNA11
Clinical Utility:
Somatic mutations in either GNA11 or GNAQ genes are identified in the majority of uveal melanoma cases.
Gene:
GNAQ
Clinical Utility:
Somatic mutations in either GNA11 or GNAQ genes are identified in the majority of uveal melanoma cases.
Gene:
GNAS
Clinical Utility:
Mutations are specific to uveal melanoma and other non-cutaneous melanomas, are not found in normal tissues, thus making them potential therapeutic targets.
Gene:
HRAS
Clinical Utility:
RAS proteins (KRAS4A, KRAS4B, NRAS and HRAS) function as GDP–GTP-regulated binary on-off switches, which regulate cytoplasmic signaling networks that control diverse normal cellular processes. Gain-of-function missense mutations in RAS genes are found in ∼25% of human cancers, prompting interest in identifying anti-RAS therapeutic strategies for cancer treatment. RAS mutations have a high positive
predictive value for malignancy in thyroid tumors, and aid in diagnosis of follicular thyroid lesions.
Gene:
IDH1
Clinical Utility:
IDH (IDH1 and IDH2) mutations are more prevalent in low grade diffuse gliomas and in secondary glioblastomas, they are associated with improved prognosis in low grade gliomas, and may predict response to therapy (IDH inhibitors, temolozomide). In acute myeloid leukemia (AML), somatic mutations in IDH1 and IDH2 are highly recurrent and are almost exclusively heterozygous and occur more frequently in AML
in normal cytogenetics.
Gene:
IDH2
Clinical Utility:
IDH (IDH1 and IDH2) mutations are more prevalent in low grade diffuse gliomas and in secondary glioblastomas, they are associated with improved prognosis in low grade gliomas, and may predict response to therapy (IDH inhibitors, temolozomide). In acute myeloid leukemia (AML), somatic mutations in IDH1 and IDH2 are highly recurrent and are almost exclusively heterozygous and occur more frequently in AML
in normal cytogenetics.
Gene:
KDR
Clinical Utility:
KDR encodes one of the two receptors of the vascular endothelial growth factor (VEGF), which is a major growth factor for endothelial cells. Mutations of this gene are implicated in infantile capillary hemangiomas.
Gene:
KIT
Clinical Utility:
In GISTs, KIT mutations predict response to TKIs (imatinib, sunitinib), with secondary mutations associated with resistance. In metastatic melanoma cases, limited response to imatinib has been reported.
Gene:
KRAS
Clinical Utility:
KRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab). In NSCLC, KRAS mutations are associated with primary EGFR TKI resistance. In breast cancer, KRAS mRNA expression was found to be an independent prognostic factor. Prognostic role of KRAS mRNA expression was effective only in luminal A subtype breast cancer.
Gene:
MEN1
Clinical Utility:
Multiple endocrine neoplasia type 1 (MEN1) is a hereditary condition associated with tumors of the endocrine (hormone producing) glands. A mutation in MEN1 gene gives a person an increased risk of developing endocrine tumors. The most common tumors seen in MEN1 involve the parathyroid gland, islet cells of the pancreas, and pituitary gland. Other endocrine tumors seen in MEN1 include adrenal cortical tumors, neuroendocrine tumors (previously called carcinoid tumors), and rare pheochromocytomas, as well as tumors in other parts of the digestive tract.
Gene:
MET
Clinical Utility:
MET alterations in solid tumors, including amplification and mutations, may predict response to MET inhibitors. MET amplification has been associated with acquired resistance to anti-EGFR TKIs in lung cancer.
Gene:
MLH1
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. DNA mismatch repair (MMR) overexpression is common in prostate cancer and is linked to poor outcome as well as features indicating genetic instability. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors, whereas others have reported somatic hypermethylation of the MLH1 gene promoter, which is associated with MLH1 gene inactivation, in as many as 52% of colon tumors. Microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest potential vulnerability to PD-1 inhibitors.
Gene:
MSH2
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer; Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
Gene:
MSH6
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. MSH6 is associated with an increased risk for breast cancer, and should be considered when ordering genetic testing for individuals who have a
personal and/or family history of breast cancer.
Gene:
NOTCH1
Clinical Utility:
NOTCH1 mutations may be associated with poor prognosis in a subset of NSCLC. NOTCH1 may contribute to TKI resistance in NSCLC. About 4-15% of Chronic lymphocytic leukemia (CLL) harbor mutations in NOTCH1. NOTCH1 mutations are more frequent in IGVH-unmutated cases nad been associated with disease progression. More specifically, NOTCH1 mutations have been found in up to 42% of trisomy 12 CLL cases.
Gene:
NRAS
Clinical Utility:
Mutations and overexpression of the neuroblastoma RAS viral (v‐ras) oncogene homolog (NRAS) are found across multiple tumor types and are common in highly metastatic cancers such as tumors of unknown primary, melanomas, and sarcomas that display a striking propensity for lung metastasis. Clinical studies suggest that patients with NRAS‐mutant or amplified tumors suffer from more aggressive disease than patients with wild‐type NRAS alleles.NRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab), and may predict response to MEK inhibitors in metastatic
melanoma.
Gene:
PDGFRA
Clinical Utility:
PDGFRA mutations predict response to TKIs (imatinib, sunitinib).
Gene:
PIK3CA
Clinical Utility:
Mutations in PIK3CA may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
PMS2
Clinical Utility:
Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors. Additionally, lynch syndrome patients with PMS2 mutations may be at a higher risk of developing breast cancer. In prostate cancer, PMS2 plays a tumor suppresor role by enhancing apoptosis in prostate cancer cells.
Gene:
POLE
Clinical Utility:
POLE/POLD1 gene variants have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutational burden (TMB), an effective indicator for response prediction in immunotherapy.
Gene:
PTEN
Clinical Utility:
Mutations in PTEN may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
PTPN11
Clinical Utility:
Mutations in PTPN11 occur in several types of hematologic malignancies, most frequently in patients with JMML.
Gene:
RB1
Clinical Utility:
Retinoblastoma 1 (RB1) is a gene that encodes a protein that is a negative regulator of the cell cycle as well as a tumor suppressor. Missense mutations, nonsense mutations, silent mutations, frameshift deletions and insertions, and in-frame deletions are observed in cancers such as cancers of the fallopian tubes, cancers of the eye, and intestinal cancer. RB1 is altered in 4.03% of all cancers with lung adenocarcinoma, breast invasive ductal carcinoma, small cell lung carcinoma, bladder urothelial carcinoma, and colon adenocarcinoma having the greatest prevalence of alterations
Gene:
RET
Clinical Utility:
RET abnormalities, including rearrangements and mutations, predict response to multi-kinase inhibitors. RET point mutations have been associated with adverse prognosis in sporadic medullary thyroid carcinomas.
Gene:
SMAD4
Clinical Utility:
A tumor suppressor gene found in at least 26 types of cancer, with higher frequencies in GI tract cancers, such as esophagus, stomach, pancrease and colorectal cancers. Additionally, loss of SMAD4 in tumors affects cancer progression and therapy, such as reduced response to adjuvant chemotherapy.
Gene:
SMO
Clinical Utility:
The G protein-coupled receptor (GPCR) smoothened (SMO) is a key signaling component of the sonic hedgehog (Hh) pathway and a clinically validated target for cancer treatment. Curently FDA-approved SMO inhibitors are GDC-0449/Vismodegib and LDE225/Sonidegib.
Gene:
SRC
Clinical Utility:
SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) is an important driver of YAP/TAZ activity in human breast cancer and melanoma cells. SRC activation increased YAP/TAZ activity and the expression of YAP/TAZ-regulated genes.
Gene:
STK11
Clinical Utility:
STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. In one clinical study, it was found that STK11/LKB1 alterations is the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Mutations in this gene have been associated with Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by the growth of polyps in the gastrointestinal tract, pigmented macules on the skin and mouth, and other neoplasms. Several published reports have demonstrated the PJS predisposes carriers to cancers of the gastrointestinal tract, as well as susceptibility to a variety of tumors.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
TSC1
Clinical Utility:
TSC1 or TSC2 mutation is responsible for Tuberous sclerosis complex, which is an autosomal dominant disorder characterized by skin manifestation and formation of multiple tumors in different organs, mainly in the central nervous system.
Gene:
TSC2
Clinical Utility:
TSC1 or TSC2 mutation is responsible for Tuberous sclerosis complex, which is an autosomal dominant disorder characterized by skin manifestation and formation of multiple tumors in different organs, mainly in the central nervous system.
Gene:
TP53
Clinical Utility:
Somatic mutations in the TP53 gene are found in the majority of human cancers, and are generally associated with adverse prognostic characteristics in a number of tumor types.
Gene:
VHL
Clinical Utility:
VHL mutations predispose to the development of a variety of tumours (most commonly retinal and central nervous system haemangioblastomas, clear cell renal carcinoma and phaeochromocytomas). Central nervous system hemangioblastoma (CHB) is the most common manifestation of VHL disease. The germline mutations in the VHL tumor suppressor gene are responsible for the inherited cancer predisposition syndrome or Von-Hippel-Lindau (VHL) disease.

OnkoSight AdvancedTM Prostate Cancer Panel (17 genes), TMB and
MSI
Test Code: TH48-2

ARATMBRCA1BRCA2 CHEK2EPCAMFANCAHOXB13MLH1
MSH2MSH6NTRK1PALB2PMS2PTENRAD51DTERT
Gene:
AKT1
Clinical Utility:
AKT1 mutations may predict response to AKT1/mTOR inhibitors.
Gene:
ALK
Clinical Utility:
Rearrangements of the ALK gene in NSCLC predict therapeutic response to ALK kinase inhibitors, including FDA-approved crizotinib and ceritinib, and resistance to EGFR inhibitors. Secondary ALK mutations and gene amplifications are associated with acquired resistance to crizotinib and variable response to second-generation ALK inhibitors.
Gene:
BRAF
Clinical Utility:
Some mutations in BRAF predict response to RAF inhibitors in a variety of solid tumors. Therapies targeting BRAF V600-mutated melanoma (vemurafenib, dabrafenib, and trametinib) have been approved by the FDA. BRAF V600E is a negative prognostic marker in colorectal cancers, with resistance to anti-EGFR therapy in some clinical settings. In CNS neoplasms, BRAF V600E mutations are rarely found in adult gliomas
with only 1% to 2 % mutated samples in glioblastomas and 2% to 5% in low grade adult gliomas. Even though a clear prognostic difference could not be established yet, BRAF V600E mutant glioblastomas have some distinct histopathological and molecular features. BRAF mutations are in most instances mutually exclusive to canonical IDH mutations.
Gene:
DDR2
Clinical Utility:
In squamous cell lung cancer, DDR2 mutations may predict response to dasatinib and other receptor tyrosine kinase inhibitors.
Gene:
EGFR
Clinical Utility:
EGFR belongs to a family of four tyrosine kinases that encompasses ErbB1 (EGFR, HER1), ErbB2 (Her-2, Neu), ErbB3 (Her-3) and ErbB4 (Her-4). Amplifications and mutations in EGFR (HER1) were detected in 45–57% of GBM cases, indicating a causal role in the pathogenesis of GBM. EGFRs induce proliferation and have been implied in glioblastoma pathogenesis and resistance to treatment. EGFR is considered a potential therapeutic target for anti-EGFR therapy in triple-negative breast cancer (TNBC). Sensitizing EGFR mutations predict response to EGFR TKIs in NSCLC, including FDA-approved TKIs (erlotinib, gefitinib and afatinib), while other mutations predict resistance to first and second generation TKIs.
Gene:
ERBB2
Clinical Utility:
Mutations in ERBB2 (HER2) are emerging targets associated with response to anti-HER2 antibody (trastuzumab) or TKI (afatinib) therapy in NSCLC. In breast cancer, ERBB2 over-expression or gene amplification is associated with response to established anti-HER2 targeted therapies. In CNS neoplasms, ErbB2/HER-2 mutation have been detected in 8–41% of glioblastoma cases.
Gene:
FGFR1
Clinical Utility:
Amplification of the FGFR1 gene predicts response to FGFR inhibition in several malignancies.
Gene:
KRAS
Clinical Utility:
KRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab). In NSCLC, KRAS mutations are associated with primary EGFR TKI resistance. In breast cancer, KRAS mRNA expression was found to be an independent prognostic factor. Prognostic role of KRAS mRNA expression was effective only in luminal A subtype breast cancer.
Gene:
MAP2K1
Clinical Utility:
MAP2K1 mutations may confer resistance to BRAF and MEK inhibitors.
Gene:
MET
Clinical Utility:
MET alterations in solid tumors, including amplification and mutations, may predict response to MET inhibitors. MET amplification has been associated with acquired resistance to anti-EGFR TKIs in lung cancer.
Gene:
NRAS
Clinical Utility:
Mutations and overexpression of the neuroblastoma RAS viral (v‐ras) oncogene homolog (NRAS) are found across multiple tumor types and are common in highly metastatic cancers such as tumors of unknown primary, melanomas, and sarcomas that display a striking propensity for lung metastasis. Clinical studies suggest that patients with NRAS‐mutant or amplified tumors suffer from more aggressive disease than patients with wild‐type NRAS alleles.NRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab), and may predict response to MEK inhibitors in metastatic melanoma.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PIK3CA
Clinical Utility:
Mutations in PIK3CA may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
POLD1
Clinical Utility:
POLE/POLD1 gene variants have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutational burden (TMB), an effective indicator for response prediction in immunotherapy.
Gene:
POLE
Clinical Utility:
POLE/POLD1 gene variants have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutational burden (TMB), an effective indicator for response prediction in immunotherapy.
Gene:
STK11
Clinical Utility:
STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. In one clinical study, it was found that STK11/LKB1 alterations is the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Mutations in this gene have been associated with Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by the growth of polyps in the gastrointestinal tract, pigmented macules on the skin and mouth, and other neoplasms. Several published reports have demonstrated the PJS predisposes carriers to cancers of the gastrointestinal tract, as well as susceptibility to a variety of tumors.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
TP53
Clinical Utility:
Somatic mutations in the TP53 gene are found in the majority of human cancers, and are generally associated with adverse prognostic characteristics in a number of tumor types.
Gene:
AR
Clinical Utility:
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and ZBTB7A that recruits NCOR1 and NCOR2 to the androgen response elements/ARE on target genes, negatively regulating androgen receptor signaling and androgen-induced cell proliferation.
Gene:
ATM
Clinical Utility:
A DNA-damage response gene that is commonly mutated in cancer. Germline mutations in this gene are thought to contribute to breast cancer susceptibility, and PARP inhibition is currently being studied for it’s potential in treating these patients. In lymphoid neoplasms, somatic mutations of ATM occur frequently in mantle cell lymphomas (MCL), chronic lymphoblastic leukemia (CLL) and T-cell prolymphocytic leukemia (TPLL).
Gene:
BRCA1
Clinical Utility:
In advance disease setting, mutations in homologous recombination repair genes such as BRCA1 and BRCA2 suggest candidacy for platinum chemotherapy and PARP inhibitor trials.
Gene:
BRCA2
Clinical Utility:
In advance disease setting, mutations in homologous recombination repair genes such as BRCA1 and BRCA2 suggest candidacy for platinum chemotherapy and PARP inhibitor trials.
Gene:
CHEK2
Clinical Utility:
Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors
Gene:
EPCAM
Clinical Utility:
The Epithelial Cell Adhesion Molecule (EpCAM) has been shown to be strongly expressed in human breast cancer and cancer stem cells and its overexpression has been supposed to support tumor progression and metastasis. Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. EPCAM overexpression may be correlated with the
development of bone metastasis and worse biochemical recurrence free-survival of PCa.
Gene:
FANCA
Clinical Utility:
The FANCA gene is one of the genes in which mutations lead to Fanconi anaemia, a rare autosomal recessive disorder characterised by congenital abnormalities, bone marrow failure, and predisposition to malignancy. FANCA is also a potential breast and ovarian cancer susceptibility gene. Associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. Defects in genes involved in DNA damage repair (DDR) pathway are emerging as novel biomarkers and targets for new prostate cancer drug therapies.
Gene:
HOXB13
Clinical Utility:
HOXB13, a member of the homeobox proteins family, is a key regulator of the epithelial differentiation in the prostate gland. HOXB13 is overexpressed during malignant progression of the prostatic tissue and suspected to contribute in the pathogenesis of the prostate gland. HOXB13 together with BRCA2 mutations have been consistently shown to increase prostate cancer risk, and are more commonly observed among patients diagnosed with early-onset disease.
Gene:
MLH1
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. DNA mismatch repair (MMR) overexpression is common in prostate cancer and is linked to poor outcome as well as features indicating genetic instability. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors, whereas others have reported somatic hypermethylation of the MLH1 gene promoter, which is associated with MLH1 gene inactivation, in as many as 52% of colon tumors. Microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest potential vulnerability to PD-1 inhibitors.
Gene:
MSH2
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer; Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
Gene:
MSH6
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. MSH6 is associated with an increased risk for breast cancer, and should be considered when ordering genetic testing for individuals who have a
personal and/or family history of breast cancer.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PALB2
Clinical Utility:
PALB2 (Partner and Localizer of Breast Cancer 2 (BRCA2)) plays an important role in maintaining genome integrity through its role in the Fanconi anemia (FA) and homologous recombination (HR) DNA repair pathways. PALB2 has emerged as a pivotal tumor suppressor protein associated to hereditary cancer susceptibility to breast and pancreatic cancers. In advanced disease setting for prostate cancer, mutations in homologous recombination repair genes (eg, BRCA1, BRCA2, ATM, CHEK2, PALB2) suggest candidacy for platinum chemotherapy and PARP inhibitor trials.
Gene:
PMS2
Clinical Utility:
Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors. Additionally, lynch syndrome patients with PMS2 mutations may be at a higher risk of developing breast cancer. In prostate cancer, PMS2 plays a tumor suppressor role by enhancing apoptosis in prostate cancer cells.
Gene:
PTEN
Clinical Utility:
Mutations in PTEN may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
RAD51D
Clinical Utility:
Recent data indicate that men with prostate cancer may have germline mutations in 1 of 16 DNA repair genes including RAD51D (0.4%). Men with these inherited syndromes have an increased risk for prostate cancer. RAD51D germline mutations have been recently associated with ovarian and breast cancer.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival
compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
AKT1
Clinical Utility:
AKT1 mutations may predict response to AKT1/mTOR inhibitors.
Gene:
ALK
Clinical Utility:
Rearrangements of the ALK gene in NSCLC predict therapeutic response to ALK kinase inhibitors, including FDA-approved crizotinib and ceritinib, and resistance to EGFR inhibitors. Secondary ALK mutations and gene amplifications are associated with acquired resistance to crizotinib and variable response to second-generation ALK inhibitors.
Gene:
APC
Clinical Utility:
Tumor suppressor. Promotes rapid degradation of CTNNB1 and participates in Wnt signaling as a negative regulator. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells.
Gene:
ARID1A
Clinical Utility:
ARID1A is mutated in over 50% of ovarian clear cell carcinomas and 30% of ovarian endometrioid carcinomas. ARID1A mutation is a known genetic driver of ovarian cancer. Over 90% of the ARID1A mutations observed in ovarian cancer are frame-shift or nonsense mutations that result in loss of ARID1A protein expression. Loss of ARID1A correlates with late-stage disease and predicts early recurrence of ovarian clear cell carcinoma.
Gene:
ATM
Clinical Utility:
A DNA-damage response gene that is commonly mutated in cancer. Germline mutations in this gene are thought to contribute to breast cancer susceptibility, and PARP inhibition is currently being studied for it’s potential in treating these patients. In lymphoid neoplasms, somatic mutations of ATM occur frequently in mantle cell lymphomas (MCL), chronic lymphoblastic leukemia (CLL) and T-cell prolymphocytic
leukemia (TPLL).
Gene:
BRAF
Clinical Utility:
Some mutations in BRAF predict response to RAF inhibitors in a variety of solid tumors. Therapies targeting BRAF V600-mutated melanoma (vemurafenib, dabrafenib, and trametinib) have been approved by the FDA. BRAF V600E is a negative prognostic marker in colorectal cancers, with resistance to anti-EGFR therapy in some clinical settings. In CNS neoplasms, BRAF V600E mutations are rarely found in adult gliomas
with only 1% to 2 % mutated samples in glioblastomas and 2% to 5% in low grade adult gliomas. Even though a clear prognostic difference could not be established yet, BRAF V600E mutant glioblastomas have some distinct histopathological and molecular features. BRAF mutations are in most instances mutually exclusive to canonical IDH mutations.
Gene:
CDH1
Clinical Utility:
Involved in mechanisms regulating cell-cell adhesions, mobility and proliferation of epithelial cells. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis
Gene:
CDKN2A
Clinical Utility:
Loss of CDKN2A is common in lymphoid neoplasms, has prognostic implications in some malignancies, and presents a therapeutic target for CDK4/6 inhibitors.
Gene:
CTNNB1
Clinical Utility:
Activating CTNNB1 mutations may predict response to WNT inhibitors.
Gene:
EGFR
Clinical Utility:
EGFR belongs to a family of four tyrosine kinases that encompasses ErbB1 (EGFR, HER1), ErbB2 (Her-2, Neu), ErbB3 (Her-3) and ErbB4 (Her-4). Amplifications and mutations in EGFR (HER1) were detected in 45–57% of GBM cases, indicating a causal role in the pathogenesis of GBM. EGFRs induce proliferation and have been implied in glioblastoma pathogenesis and resistance to treatment. EGFR is considered a potential therapeutic target for anti-EGFR therapy in triple-negative breast cancer (TNBC). Sensitizing EGFR mutations predict response to EGFR TKIs in NSCLC, including FDA-approved TKIs (erlotinib, gefitinib and afatinib), while other mutations predict resistance to first and second generation TKIs.
Gene:
EPCAM
Clinical Utility:
The Epithelial Cell Adhesion Molecule (EpCAM) has been shown to be strongly expressed in human breast cancer and cancer stem cells and its overexpression has been supposed to support tumor progression and metastasis. Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. EPCAM overexpression may be correlated with the
development of bone metastasis and worse biochemical recurrence free-survival of PCa.
Gene:
ERBB2
Clinical Utility:
Mutations in ERBB2 (HER2) are emerging targets associated with response to anti-HER2 antibody (trastuzumab) or TKI (afatinib) therapy in NSCLC. In breast cancer, ERBB2 over-expression or gene amplification is associated with response to established anti-HER2 targeted therapies. In CNS neoplasms, ErbB2/HER-2 mutation have been detected in 8–41% of glioblastoma cases.
Gene:
ERBB4
Clinical Utility:
The ErbB signalling network plays a crucial role in the growth and progression of several cancers, including colorectal cancer (CRC), and includes potentially drug-targetable genes. Oncogenic activation of the ErbB pathway by mutations and focal amplifications have emerged recently as an important predictive marker of the prognosis of CRC patients.
Gene:
FBXW7
Clinical Utility:
Mutations in the FBXW7 tumor suppressor have been observed in some hematological malignancies, including CLL and T-ALL.
Gene:
FGFR1
Clinical Utility:
Amplification of the FGFR1 gene predicts response to FGFR inhibition in several malignancies.
Gene:
FGFR2
Clinical Utility:
Alterations of FGFR2, including amplification, rearrangements and point mutations, predict response to FGFR inhibition in several malignancies.
Gene:
FGFR3
Clinical Utility:
Alterations of FGFR3, including amplification, rearrangements and point mutations, predict response to FGFR inhibition in several malignancies.
Gene:
GNA11
Clinical Utility:
Somatic mutations in either GNA11 or GNAQ genes are identified in the majority of uveal melanoma cases.
Gene:
GNAQ
Clinical Utility:
Somatic mutations in either GNA11 or GNAQ genes are identified in the majority of uveal melanoma cases.
Gene:
GNAS
Clinical Utility:
Mutations are specific to uveal melanoma and other non-cutaneous melanomas, are not found in normal tissues, thus making them potential therapeutic targets.
Gene:
HRAS
Clinical Utility:
RAS proteins (KRAS4A, KRAS4B, NRAS and HRAS) function as GDP–GTP-regulated binary on-off switches, which regulate cytoplasmic signaling networks that control diverse normal cellular processes. Gain-of-function missense mutations in RAS genes are found in ∼25% of human cancers, prompting interest in identifying anti-RAS therapeutic strategies for cancer treatment. RAS mutations have a high positive
predictive value for malignancy in thyroid tumors, and aid in diagnosis of follicular thyroid lesions.
Gene:
IDH1
Clinical Utility:
IDH (IDH1 and IDH2) mutations are more prevalent in low grade diffuse gliomas and in secondary glioblastomas, they are associated with improved prognosis in low grade gliomas, and may predict response to therapy (IDH inhibitors, temolozomide). In acute myeloid leukemia (AML), somatic mutations in IDH1 and IDH2 are highly recurrent and are almost exclusively heterozygous and occur more frequently in AML
in normal cytogenetics.
Gene:
IDH2
Clinical Utility:
IDH (IDH1 and IDH2) mutations are more prevalent in low grade diffuse gliomas and in secondary glioblastomas, they are associated with improved prognosis in low grade gliomas, and may predict response to therapy (IDH inhibitors, temolozomide). In acute myeloid leukemia (AML), somatic mutations in IDH1 and IDH2 are highly recurrent and are almost exclusively heterozygous and occur more frequently in AML
in normal cytogenetics.
Gene:
KDR
Clinical Utility:
KDR encodes one of the two receptors of the vascular endothelial growth factor (VEGF), which is a major growth factor for endothelial cells. Mutations of this gene are implicated in infantile capillary hemangiomas.
Gene:
KIT
Clinical Utility:
In GISTs, KIT mutations predict response to TKIs (imatinib, sunitinib), with secondary mutations associated with resistance. In metastatic melanoma cases, limited response to imatinib has been reported.
Gene:
KRAS
Clinical Utility:
KRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab). In NSCLC, KRAS mutations are associated with primary EGFR TKI resistance. In breast cancer, KRAS mRNA expression was found to be an independent prognostic factor. Prognostic role of KRAS mRNA expression was effective only in luminal A subtype breast cancer.
Gene:
MEN1
Clinical Utility:
Multiple endocrine neoplasia type 1 (MEN1) is a hereditary condition associated with tumors of the endocrine (hormone producing) glands. A mutation in MEN1 gene gives a person an increased risk of developing endocrine tumors. The most common tumors seen in MEN1 involve the parathyroid gland, islet cells of the pancreas, and pituitary gland. Other endocrine tumors seen in MEN1 include adrenal cortical umors, neuroendocrine tumors (previously called carcinoid tumors), and rare pheochromocytomas, as well as tumors in other parts of the digestive tract.
Gene:
MET
Clinical Utility:
MET alterations in solid tumors, including amplification and mutations, may predict response to MET inhibitors. MET amplification has been associated with acquired resistance to anti-EGFR TKIs in lung cancer.
Gene:
MLH1
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. DNA mismatch repair (MMR) overexpression is common in prostate cancer and is linked to poor outcome as well as features indicating genetic instability. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors, whereas others have
reported somatic hypermethylation of the MLH1 gene promoter, which is associated with MLH1 gene inactivation, in as many as 52% of colon tumors. Microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest potential vulnerability to PD-1 inhibitors.
Gene:
MSH2
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer; Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
Gene:
MSH6
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. MSH6 is associated with an increased risk for breast cancer, and should be considered when ordering genetic testing for individuals who have a
personal and/or family history of breast cancer.
Gene:
NOTCH1
Clinical Utility:
NOTCH1 mutations may be associated with poor prognosis in a subset of NSCLC. NOTCH1 may contribute to TKI resistance in NSCLC. About 4-15% of Chronic lymphocytic leukemia (CLL) harbor mutations in NOTCH1. NOTCH1 mutations are more frequent in IGVH-unmutated cases nad been associated with disease progression. More specifically, NOTCH1 mutations have been found in up to 42% of trisomy 12 CLL cases.
Gene:
NRAS
Clinical Utility:
Mutations and overexpression of the neuroblastoma RAS viral (v‐ras) oncogene homolog (NRAS) are found across multiple tumor types and are common in highly metastatic cancers such as tumors of unknown primary, melanomas, and sarcomas that display a striking propensity for lung metastasis. Clinical studies suggest that patients with NRAS‐mutant or amplified tumors suffer from more aggressive disease than patients with wild‐type NRAS alleles.NRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab), and may predict response to MEK inhibitors in metastatic melanoma.
Gene:
PDGFRA
Clinical Utility:
PDGFRA mutations predict response to TKIs (imatinib, sunitinib).
Gene:
PIK3CA
Clinical Utility:
Mutations in PIK3CA may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
PMS2
Clinical Utility:
Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors. Additionally, lynch syndrome patients with PMS2 mutations may be at a higher risk of developing breast cancer. In prostate cancer, PMS2 plays a tumor suppressor role by enhancing apoptosis in prostate cancer cells.
Gene:
POLE
Clinical Utility:
POLE/POLD1 gene variants have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutational burden (TMB), an effective indicator for response prediction in immunotherapy.
Gene:
PTEN
Clinical Utility:
Mutations in PTEN may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
PTPN11
Clinical Utility:
Mutations in PTPN11 occur in several types of hematologic malignancies, most frequently in patients with JMML.
Gene:
RB1
Clinical Utility:
Retinoblastoma 1 (RB1) is a gene that encodes a protein that is a negative regulator of the cell cycle as well as a tumor suppressor. Missense mutations, nonsense mutations, silent mutations, frameshift deletions and insertions, and in-frame deletions are observed in cancers such as cancers of the fallopian tubes, cancers of the eye, and intestinal cancer. RB1 is altered in 4.03% of all cancers with lung adenocarcinoma, breast invasive ductal carcinoma, small cell lung carcinoma, bladder urothelial carcinoma, and colon adenocarcinoma having the greatest prevalence of alterations.
Gene:
RET
Clinical Utility:
RET abnormalities, including rearrangements and mutations, predict response to multi-kinase inhibitors. RET point mutations have been associated with adverse prognosis in sporadic medullary thyroid carcinomas.
Gene:
SMAD4
Clinical Utility:
A tumor suppressor gene found in at least 26 types of cancer, with higher frequencies in GI tract cancers, such as esophagus, stomach, pancrease and colorectal cancers. Additionally, loss of SMAD4 in tumors affects cancer progression and therapy, such as reduced response to adjuvant chemotherapy.
Gene:
SMO
Clinical Utility:
The G protein-coupled receptor (GPCR) smoothened (SMO) is a key signaling component of the sonic hedgehog (Hh) pathway and a clinically validated target for cancer treatment. Curently FDA-approved SMO inhibitors are GDC-0449/Vismodegib and LDE225/Sonidegib.
Gene:
SRC
Clinical Utility:
SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) is an important driver of YAP/TAZ activity in human breast cancer and melanoma cells. SRC activation increased YAP/TAZ activity and the expression of YAP/TAZ-regulated genes.
Gene:
STK11
Clinical Utility:
STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. In one clinical study, it was found that STK11/LKB1 alterations is the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Mutations in this gene have been associated with Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by the growth of polyps in the gastrointestinal tract, pigmented macules on the skin and mouth, and other neoplasms. Several published reports have demonstrated the PJS predisposes carriers to cancers of the gastrointestinal tract, as well as susceptibility to a variety of tumors.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival
compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
TSC1
Clinical Utility:
TSC1 or TSC2 mutation is responsible for Tuberous sclerosis complex, which is an autosomal dominant disorder characterized by skin manifestation and formation of multiple tumors in different organs, mainly in the central nervous system.
Gene:
TSC2
Clinical Utility:
TSC1 or TSC2 mutation is responsible for Tuberous sclerosis complex, which is an autosomal dominant disorder characterized by skin manifestation and formation of multiple tumors in different organs, mainly in the central nervous system.
Gene:
TP53
Clinical Utility:
Somatic mutations in the TP53 gene are found in the majority of human cancers, and are generally associated with adverse prognostic characteristics in a number of tumor types.
Gene:
VHL
Clinical Utility:
VHL mutations predispose to the development of a variety of tumours (most commonly retinal and central nervous system haemangioblastomas, clear cell renal carcinoma and phaeochromocytomas). Central nervous system hemangioblastoma (CHB) is the most common manifestation of VHL disease. The germline mutations in the VHL tumor suppressor gene are responsible for the inherited cancer predisposition syndrome or Von-Hippel-Lindau (VHL) disease.

OnkoSight AdvancedTM Solid Tumor Panel (50 genes), TMB and
MSI
Test Code: TJ16-5

AKT1ALKAPCARID1AATMBRAFCDH1CDKN2ACTNNB1
EGFREPCAMERBB2ERBB4FBXW7FGFR1FGFR2FGFR3GNA11
GNAQGNASHRASIDH1IDH2KDRKITKRASMEN1
METMLH1MSH2MSH6NOTCH1NRASPDGFRAPIK3CAPMS2
POLEPTENPTPN11RB1RETSMAD4SMOSRCSTK11
TERTTSC1TSC2TP53VHL
Gene:
AKT1
Clinical Utility:
AKT1 mutations may predict response to AKT1/mTOR inhibitors.
Gene:
ALK
Clinical Utility:
Rearrangements of the ALK gene in NSCLC predict therapeutic response to ALK kinase inhibitors, including FDA-approved crizotinib and ceritinib, and resistance to EGFR inhibitors. Secondary ALK mutations and gene amplifications are associated with acquired resistance to crizotinib and variable response to second-generation ALK inhibitors.
Gene:
BRAF
Clinical Utility:
Some mutations in BRAF predict response to RAF inhibitors in a variety of solid tumors. Therapies targeting BRAF V600-mutated melanoma (vemurafenib, dabrafenib, and trametinib) have been approved by the FDA. BRAF V600E is a negative prognostic marker in colorectal cancers, with resistance to anti-EGFR therapy in some clinical settings. In CNS neoplasms, BRAF V600E mutations are rarely found in adult gliomas
with only 1% to 2 % mutated samples in glioblastomas and 2% to 5% in low grade adult gliomas. Even though a clear prognostic difference could not be established yet, BRAF V600E mutant glioblastomas have some distinct histopathological and molecular features. BRAF mutations are in most instances mutually exclusive to canonical IDH mutations.
Gene:
DDR2
Clinical Utility:
In squamous cell lung cancer, DDR2 mutations may predict response to dasatinib and other receptor tyrosine kinase inhibitors.
Gene:
EGFR
Clinical Utility:
EGFR belongs to a family of four tyrosine kinases that encompasses ErbB1 (EGFR, HER1), ErbB2 (Her-2, Neu), ErbB3 (Her-3) and ErbB4 (Her-4). Amplifications and mutations in EGFR (HER1) were detected in 45–57% of GBM cases, indicating a causal role in the pathogenesis of GBM. EGFRs induce proliferation and have been implied in glioblastoma pathogenesis and resistance to treatment. EGFR is considered a potential therapeutic target for anti-EGFR therapy in triple-negative breast cancer (TNBC). Sensitizing EGFR mutations predict response to EGFR TKIs in NSCLC, including FDA-approved TKIs (erlotinib, gefitinib and afatinib), while other mutations predict resistance to first and second generation TKIs.
Gene:
ERBB2
Clinical Utility:
Mutations in ERBB2 (HER2) are emerging targets associated with response to anti-HER2 antibody (trastuzumab) or TKI (afatinib) therapy in NSCLC. In breast cancer, ERBB2 over-expression or gene amplification is associated with response to established anti-HER2 targeted therapies. In CNS neoplasms, ErbB2/HER-2 mutation have been detected in 8–41% of glioblastoma cases.
Gene:
FGFR1
Clinical Utility:
Amplification of the FGFR1 gene predicts response to FGFR inhibition in several malignancies.
Gene:
KRAS
Clinical Utility:
KRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab). In NSCLC, KRAS mutations are associated with primary EGFR TKI resistance. In breast cancer, KRAS mRNA expression was found to be an independent prognostic factor. Prognostic role of KRAS mRNA expression was effective only in luminal A subtype breast cancer.
Gene:
MAP2K1
Clinical Utility:
MAP2K1 mutations may confer resistance to BRAF and MEK inhibitors.
Gene:
MET
Clinical Utility:
MET alterations in solid tumors, including amplification and mutations, may predict response to MET inhibitors. MET amplification has been associated with acquired resistance to anti-EGFR TKIs in lung cancer.
Gene:
NRAS
Clinical Utility:
Mutations and overexpression of the neuroblastoma RAS viral (v‐ras) oncogene homolog (NRAS) are found across multiple tumor types and are common in highly metastatic cancers such as tumors of unknown primary, melanomas, and sarcomas that display a striking propensity for lung metastasis. Clinical studies suggest that patients with NRAS‐mutant or amplified tumors suffer from more aggressive disease than
patients with wild‐type NRAS alleles.NRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab), and may predict response to MEK inhibitors in metastatic melanoma.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PIK3CA
Clinical Utility:
Mutations in PIK3CA may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
POLD1
Clinical Utility:
POLE/POLD1 gene variants have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutational burden (TMB), an effective indicator for response prediction in immunotherapy.
Gene:
POLE
Clinical Utility:
POLE/POLD1 gene variants have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutational burden (TMB), an effective indicator for response prediction in immunotherapy.
Gene:
STK11
Clinical Utility:
STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. In one clinical study, it was found that STK11/LKB1 alterations is the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Mutations in this gene have been associated with Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by the growth of polyps in the gastrointestinal tract, pigmented macules on the skin and mouth, and other neoplasms. Several published reports have demonstrated the PJS predisposes carriers to cancers of the  gastrointestinal tract, as well as susceptibility to a variety of tumors.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival
compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
TP53
Clinical Utility:
Somatic mutations in the TP53 gene are found in the majority of human cancers, and are generally associated with adverse prognostic characteristics in a number of tumor types.
Gene:
AR
Clinical Utility:
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and ZBTB7A that recruits NCOR1 and NCOR2 to the androgen response elements/ARE on target genes, negatively regulating androgen receptor signaling and androgen-induced cell proliferation.
Gene:
ATM
Clinical Utility:
A DNA-damage response gene that is commonly mutated in cancer. Germline mutations in this gene are thought to contribute to breast cancer susceptibility, and PARP inhibition is currently being studied for it’s potential in treating these patients. In lymphoid neoplasms, somatic mutations of ATM occur frequently in mantle cell lymphomas (MCL), chronic lymphoblastic leukemia (CLL) and T-cell prolymphocytic
leukemia (TPLL).
Gene:
BRCA1
Clinical Utility:
In advance disease setting, mutations in homologous recombination repair genes such as BRCA1 and BRCA2 suggest candidacy for platinum chemotherapy and PARP inhibitor trials.
Gene:
BRCA2
Clinical Utility:
In advance disease setting, mutations in homologous recombination repair genes such as BRCA1 and BRCA2 suggest candidacy for platinum chemotherapy and PARP inhibitor trials.
Gene:
CHEK2
Clinical Utility:
Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors.
Gene:
EPCAM
Clinical Utility:
The Epithelial Cell Adhesion Molecule (EpCAM) has been shown to be strongly expressed in human breast cancer and cancer stem cells and its overexpression has been supposed to support tumor progression and metastasis. Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. EPCAM overexpression may be correlated with the
development of bone metastasis and worse biochemical recurrence free-survival of PCa.
Gene:
FANCA
Clinical Utility:
The FANCA gene is one of the genes in which mutations lead to Fanconi anaemia, a rare autosomal recessive disorder characterised by congenital abnormalities, bone marrow failure, and predisposition to malignancy. FANCA is also a potential breast and ovarian cancer susceptibility gene. Associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. Defects in genes involved in DNA damage repair (DDR) pathway are emerging as novel biomarkers and targets for new prostate cancer drug therapies.
Gene:
HOXB13
Clinical Utility:
HOXB13, a member of the homeobox proteins family, is a key regulator of the epithelial differentiation in the prostate gland. HOXB13 is overexpressed during malignant progression of the prostatic tissue and suspected to contribute in the pathogenesis of the prostate gland. HOXB13 together with BRCA2 mutations have been consistently shown to increase prostate cancer risk, and are more commonly observed
among patients diagnosed with early-onset disease.
Gene:
MLH1
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. DNA mismatch repair (MMR) overexpression is common in prostate cancer and is linked to poor outcome as well as features indicating genetic instability. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors, whereas others have reported somatic hypermethylation of the MLH1 gene promoter, which is associated with MLH1 gene inactivation, in as many as 52% of colon tumors. Microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest potential vulnerability to PD-1 inhibitors.
Gene:
MSH2
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer; Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
Gene:
MSH6
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. MSH6 is associated with an increased risk for breast cancer, and should be considered when ordering genetic testing for individuals who have a
personal and/or family history of breast cancer.
Gene:
NTRK1
Clinical Utility:
The detection of NTRK gene fusion involving either NTRK1, NTRK2, or NTRK3, can assist in selecting patients that may benefit from TRK inhibitor therapies.
Gene:
PALB2
Clinical Utility:
PALB2 (Partner and Localizer of Breast Cancer 2 (BRCA2)) plays an important role in maintaining genome integrity through its role in the Fanconi anemia (FA) and homologous recombination (HR) DNA repair pathways. PALB2 has emerged as a pivotal tumor suppressor protein associated to hereditary cancer susceptibility to breast and pancreatic cancers. In advanced disease setting for prostate cancer, mutations
in homologous recombination repair genes (eg, BRCA1, BRCA2, ATM, CHEK2, PALB2) suggest candidacy for platinum chemotherapy and PARP inhibitor trials.
Gene:
PMS2
Clinical Utility:
Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors. Additionally, lynch syndrome patients with PMS2 mutations may be at a higher risk of developing breast cancer. In prostate cancer, PMS2 plays a tumor suppresor role by enhancing apoptosis in prostate cancer cells.
Gene:
PTEN
Clinical Utility:
Mutations in PTEN may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
RAD51D
Clinical Utility:
Recent data indicate that men with prostate cancer may have germline mutations in 1 of 16 DNA repair genes including RAD51D (0.4%). Men with these inherited syndromes have an increased risk for prostate cancer. RAD51D germline mutations have been recently associated with ovarian and breast cancer.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival
compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
AKT1
Clinical Utility:
AKT1 mutations may predict response to AKT1/mTOR inhibitors.
Gene:
ALK
Clinical Utility:
Rearrangements of the ALK gene in NSCLC predict therapeutic response to ALK kinase inhibitors, including FDA-approved crizotinib and ceritinib, and resistance to EGFR inhibitors. Secondary ALK mutations and gene amplifications are associated with acquired resistance to crizotinib and variable response to second-generation ALK inhibitors.
Gene:
APC
Clinical Utility:
Tumor suppressor. Promotes rapid degradation of CTNNB1 and participates in Wnt signaling as a negative regulator. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells.
Gene:
ARID1A
Clinical Utility:
ARID1A is mutated in over 50% of ovarian clear cell carcinomas and 30% of ovarian endometrioid carcinomas. ARID1A mutation is a known genetic driver of ovarian cancer. Over 90% of the ARID1A mutations observed in ovarian cancer are frame-shift or nonsense mutations that result in loss of ARID1A protein expression. Loss of ARID1A correlates with late-stage disease and predicts early recurrence of ovarian clear cell carcinoma.
Gene:
ATM
Clinical Utility:
A DNA-damage response gene that is commonly mutated in cancer. Germline mutations in this gene are thought to contribute to breast cancer susceptibility, and PARP inhibition is currently being studied for it’s potential in treating these patients. In lymphoid neoplasms, somatic mutations of ATM occur frequently in mantle cell lymphomas (MCL), chronic lymphoblastic leukemia (CLL) and T-cell prolymphocytic
leukemia (TPLL).
Gene:
BRAF
Clinical Utility:
Some mutations in BRAF predict response to RAF inhibitors in a variety of solid tumors. Therapies targeting BRAF V600-mutated melanoma (vemurafenib, dabrafenib, and trametinib) have been approved by the FDA. BRAF V600E is a negative prognostic marker in colorectal cancers, with resistance to anti-EGFR therapy in some clinical settings. In CNS neoplasms, BRAF V600E mutations are rarely found in adult gliomas
with only 1% to 2 % mutated samples in glioblastomas and 2% to 5% in low grade adult gliomas. Even though a clear prognostic difference could not be established yet, BRAF V600E mutant glioblastomas have some distinct histopathological and molecular features. BRAF mutations are in most instances mutually exclusive to canonical IDH mutations.
Gene:
CDH1
Clinical Utility:
Involved in mechanisms regulating cell-cell adhesions, mobility and proliferation of epithelial cells. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis
Gene:
CDKN2A
Clinical Utility:
Loss of CDKN2A is common in lymphoid neoplasms, has prognostic implications in some malignancies, and presents a therapeutic target for CDK4/6 inhibitors.
Gene:
CTNNB1
Clinical Utility:
Activating CTNNB1 mutations may predict response to WNT inhibitors.
Gene:
EGFR
Clinical Utility:
EGFR belongs to a family of four tyrosine kinases that encompasses ErbB1 (EGFR, HER1), ErbB2 (Her-2, Neu), ErbB3 (Her-3) and ErbB4 (Her-4). Amplifications and mutations in EGFR (HER1) were detected in 45–57% of GBM cases, indicating a causal role in the pathogenesis of GBM. EGFRs induce proliferation and have been implied in glioblastoma pathogenesis and resistance to treatment. EGFR is considered a potential therapeutic target for anti-EGFR therapy in triple-negative breast cancer (TNBC). Sensitizing EGFR mutations predict response to EGFR TKIs in NSCLC, including FDA-approved TKIs (erlotinib, gefitinib and afatinib), while other mutations predict resistance to first and second generation TKIs.
Gene:
EPCAM
Clinical Utility:
The Epithelial Cell Adhesion Molecule (EpCAM) has been shown to be strongly expressed in human breast cancer and cancer stem cells and its overexpression has been supposed to support tumor progression and metastasis. Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. EPCAM overexpression may be correlated with the
development of bone metastasis and worse biochemical recurrence free-survival of PCa.
Gene:
ERBB2
Clinical Utility:
Mutations in ERBB2 (HER2) are emerging targets associated with response to anti-HER2 antibody (trastuzumab) or TKI (afatinib) therapy in NSCLC. In breast cancer, ERBB2 over-expression or gene amplification is associated with response to established anti-HER2 targeted therapies. In CNS neoplasms, ErbB2/HER-2 mutation have been detected in 8–41% of glioblastoma cases.
Gene:
ERBB4
Clinical Utility:
The ErbB signalling network plays a crucial role in the growth and progression of several cancers, including colorectal cancer (CRC), and includes potentially drug-targetable genes. Oncogenic activation of the ErbB pathway by mutations and focal amplifications have emerged recently as an important predictive marker of the prognosis of CRC patients.
Gene:
FBXW7
Clinical Utility:
Mutations in the FBXW7 tumor suppressor have been observed in some hematological malignancies, including CLL and T-ALL.
Gene:
FGFR1
Clinical Utility:
Amplification of the FGFR1 gene predicts response to FGFR inhibition in several malignancies.
Gene:
FGFR2
Clinical Utility:
Alterations of FGFR2, including amplification, rearrangements and point mutations, predict response to FGFR inhibition in several malignancies.
Gene:
FGFR3
Clinical Utility:
Alterations of FGFR3, including amplification, rearrangements and point mutations, predict response to FGFR inhibition in several malignancies.
Gene:
GNA11
Clinical Utility:
Somatic mutations in either GNA11 or GNAQ genes are identified in the majority of uveal melanoma cases.
Gene:
GNAQ
Clinical Utility:
Somatic mutations in either GNA11 or GNAQ genes are identified in the majority of uveal melanoma cases.
Gene:
GNAS
Clinical Utility:
Mutations are specific to uveal melanoma and other non-cutaneous melanomas, are not found in normal tissues, thus making them potential therapeutic targets.
Gene:
HRAS
Clinical Utility:
RAS proteins (KRAS4A, KRAS4B, NRAS and HRAS) function as GDP–GTP-regulated binary on-off switches, which regulate cytoplasmic signaling networks that control diverse normal cellular processes. Gain-of-function missense mutations in RAS genes are found in ∼25% of human cancers, prompting interest in identifying anti-RAS therapeutic strategies for cancer treatment. RAS mutations have a high positive
predictive value for malignancy in thyroid tumors, and aid in diagnosis of follicular thyroid lesions.
Gene:
IDH1
Clinical Utility:
IDH (IDH1 and IDH2) mutations are more prevalent in low grade diffuse gliomas and in secondary glioblastomas, they are associated with improved prognosis in low grade gliomas, and may predict esponse to therapy (IDH inhibitors, temolozomide). In acute myeloid leukemia (AML), somatic mutations in IDH1 and IDH2 are highly recurrent and are almost exclusively heterozygous and occur more frequently in AML
in normal cytogenetics.
Gene:
IDH2
Clinical Utility:
IDH (IDH1 and IDH2) mutations are more prevalent in low grade diffuse gliomas and in secondary glioblastomas, they are associated with improved prognosis in low grade gliomas, and may predict response to therapy (IDH inhibitors, temolozomide). In acute myeloid leukemia (AML), somatic mutations in IDH1 and IDH2 are highly recurrent and are almost exclusively heterozygous and occur more frequently in AML
in normal cytogenetics.
Gene:
KDR
Clinical Utility:
KDR encodes one of the two receptors of the vascular endothelial growth factor (VEGF), which is a major growth factor for endothelial cells. Mutations of this gene are implicated in infantile capillary hemangiomas.
Gene:
KIT
Clinical Utility:
In GISTs, KIT mutations predict response to TKIs (imatinib, sunitinib), with secondary mutations associated with resistance. In metastatic melanoma cases, limited response to imatinib has been reported.
Gene:
KRAS
Clinical Utility:
KRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab). In NSCLC, KRAS mutations are associated with primary EGFR TKI resistance. In breast cancer, KRAS mRNA expression was found to be an independent prognostic factor. Prognostic role of KRAS mRNA expression was effective only in luminal A subtype breast cancer.
Gene:
MEN1
Clinical Utility:
Multiple endocrine neoplasia type 1 (MEN1) is a hereditary condition associated with tumors of the endocrine (hormone producing) glands. A mutation in MEN1 gene gives a person an increased risk of developing endocrine tumors. The most common tumors seen in MEN1 involve the parathyroid gland, islet cells of the pancreas, and pituitary gland. Other endocrine tumors seen in MEN1 include adrenal cortical tumors, neuroendocrine tumors (previously called carcinoid tumors), and rare pheochromocytomas, as well as tumors in other parts of the digestive tract.
Gene:
MET
Clinical Utility:
MET alterations in solid tumors, including amplification and mutations, may predict response to MET inhibitors. MET amplification has been associated with acquired resistance to anti-EGFR TKIs in lung cancer.
Gene:
MLH1
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. DNA mismatch repair (MMR) overexpression is common in prostate cancer and is linked to poor outcome as well as features indicating genetic instability. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors, whereas others have reported somatic hypermethylation of the MLH1 gene promoter, which is associated with MLH1 gene inactivation, in as many as 52% of colon tumors. Microsatellite instability and mismatch repair deficiency, which may arise in the setting of MLH1, MSH2, MSH6, and PMS2 mutations, suggest potential vulnerability to PD-1 inhibitors.
Gene:
MSH2
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer; Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
Gene:
MSH6
Clinical Utility:
Men with Lynch Syndrome (germline mutations in MLH1, MLH2, MSH6, PMS2, or EPCAM) have a 2- to 5.8-fold increase in risk for prostate cancer. Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. MSH6 is associated with an increased risk for breast cancer, and should be considered when ordering genetic testing for individuals who have a
personal and/or family history of breast cancer.
Gene:
NOTCH1
Clinical Utility:
NOTCH1 mutations may be associated with poor prognosis in a subset of NSCLC. NOTCH1 may contribute to TKI resistance in NSCLC. About 4-15% of Chronic lymphocytic leukemia (CLL) harbor mutations in NOTCH1. NOTCH1 mutations are more frequent in IGVH-unmutated cases nad been associated with disease progression. More specifically, NOTCH1 mutations have been found in up to 42% of trisomy 12 CLL cases.
Gene:
NRAS
Clinical Utility:
Mutations and overexpression of the neuroblastoma RAS viral (v‐ras) oncogene homolog (NRAS) are found across multiple tumor types and are common in highly metastatic cancers such as tumors of unknown primary, melanomas, and sarcomas that display a striking propensity for lung metastasis. Clinical studies suggest that patients with NRAS‐mutant or amplified tumors suffer from more aggressive disease than atients with wild‐type NRAS alleles.NRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab), and may predict response to MEK inhibitors in metastatic melanoma.
Gene:
PDGFRA
Clinical Utility:
PDGFRA mutations predict response to TKIs (imatinib, sunitinib).
Gene:
PIK3CA
Clinical Utility:
Mutations in PIK3CA may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
PMS2
Clinical Utility:
Germline mutations in the MMR genes found in individuals with Lynch Syndrome, is responsible for 2% to 4% of colon cancer cases. Somatic MMR defects have been reported to occur in approximately 19% of colorectal tumors. Additionally, lynch syndrome patients with PMS2 mutations may be at a higher risk of developing breast cancer. In prostate cancer, PMS2 plays a tumor suppressor role by enhancing apoptosis in prostate cancer cells.
Gene:
POLE
Clinical Utility:
POLE/POLD1 gene variants have been suggested as potential markers for immunotherapy due to their significant association with the tumor mutational burden (TMB), an effective indicator for response prediction in immunotherapy.
Gene:
PTEN
Clinical Utility:
Mutations in PTEN may predict response to PI3K/AKT/mTOR inhibitors.
Gene:
PTPN11
Clinical Utility:
Mutations in PTPN11 occur in several types of hematologic malignancies, most frequently in patients with JMML.
Gene:
RB1
Clinical Utility:
Retinoblastoma 1 (RB1) is a gene that encodes a protein that is a negative regulator of the cell cycle as well as a tumor suppressor. Missense mutations, nonsense mutations, silent mutations, frameshift deletions and insertions, and in-frame deletions are observed in cancers such as cancers of the fallopian tubes, cancers of the eye, and intestinal cancer. RB1 is altered in 4.03% of all cancers with lung adenocarcinoma, breast invasive ductal carcinoma, small cell lung carcinoma, bladder urothelial carcinoma, and colon adenocarcinoma having the greatest prevalence of alterations.
Gene:
RET
Clinical Utility:
RET abnormalities, including rearrangements and mutations, predict response to multi-kinase inhibitors. RET point mutations have been associated with adverse prognosis in sporadic medullary thyroid carcinomas.
Gene:
SMAD4
Clinical Utility:
A tumor suppressor gene found in at least 26 types of cancer, with higher frequencies in GI tract cancers, such as esophagus, stomach, pancrease and colorectal cancers. Additionally, loss of SMAD4  n tumors affects cancer progression and therapy, such as reduced response to adjuvant chemotherapy.
Gene:
SMO
Clinical Utility:
The G protein-coupled receptor (GPCR) smoothened (SMO) is a key signaling component of the sonic hedgehog (Hh) pathway and a clinically validated target for cancer treatment. Curently FDA-approved SMO inhibitors are GDC-0449/Vismodegib and LDE225/Sonidegib.
Gene:
SRC
Clinical Utility:
SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) is an important driver of YAP/TAZ activity in human breast cancer and melanoma cells. SRC activation increased YAP/TAZ activity and the expression of YAP/TAZ-regulated genes.
Gene:
STK11
Clinical Utility:
STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. In one clinical study, it was found that STK11/LKB1 alterations is the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Mutations in this gene have been associated with Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by the growth of polyps in the gastrointestinal tract, pigmented macules on the skin and mouth, and other neoplasms. Several published reports have demonstrated the PJS predisposes carriers to cancers of the gastrointestinal tract, as well as susceptibility to a variety of tumors.
Gene:
TERT
Clinical Utility:
Has both diagnostic and prognostic value for CNS tumors. Diagnsotic: TERT mutation, in combination with IDH mutation and 1p/19q codeletion, is characteristics of oligodendroglioma. Absence of TERT mutation, coupled with IDH mutation, designates astrocytoma. Prognostic: In the absence of IDH mutation, TERT mutations in diffusely infiltrative gliomas are associated with reduced overall survival
compared wto gliomas lacking TERT mutations. Combined TERT and IDH mutations inthe absence of 1p/19q codeletion is an uncommon eent, but such tumors have a prognosis as favorable as gliomas with all three molecular alterations. For Lung cancer, clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.) Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis.
Gene:
TSC1
Clinical Utility:
TSC1 or TSC2 mutation is responsible for Tuberous sclerosis complex, which is an autosomal dominant disorder characterized by skin manifestation and formation of multiple tumors in different organs, mainly in the central nervous system.
Gene:
TSC2
Clinical Utility:
TSC1 or TSC2 mutation is responsible for Tuberous sclerosis complex, which is an autosomal dominant disorder characterized by skin manifestation and formation of multiple tumors in different organs, mainly in the central nervous system.
Gene:
TP53
Clinical Utility:
Somatic mutations in the TP53 gene are found in the majority of human cancers, and are generally associated with adverse prognostic characteristics in a number of tumor types.
Gene:
VHL
Clinical Utility:
VHL mutations predispose to the development of a variety of tumours (most commonly retinal and central nervous system haemangioblastomas, clear cell renal carcinoma and phaeochromocytomas). Central nervous system hemangioblastoma (CHB) is the most common manifestation of VHL disease. The germline mutations in the VHL tumor suppressor gene are responsible for the inherited cancer predisposition syndrome or Von-Hippel-Lindau (VHL) disease.

HEMATOLOGIC NGS PANEL

Click on a gene below to learn more

OnkoSight AdvancedTM Chronic Lymphoid Neoplasms Panel (31 genes),
TMB and MSI
TEST CODE: TH55-7

ATMBCL2BCL6 BIRC3BRAFBTXCARD11CD79BCDKN2A
CXCR4DNMT3A EZH2IDH1IDH2JAK1 JAK3 KMT2DMAP2K1
MYD88NOTCH1NOTCH2NRASPLCG2RHOASETD2SF3B1STAT3
STAT5BTET2TNFRSF14 TP53
Gene:
ATM
Clinical Utility:
A DNA-damage response gene that is commonly mutated in cancer. Germline mutations in this gene are thought to contribute to breast cancer susceptibility, and PARP inhibition is currently being studied for it’s potential in treating these patients. In lymphoid neoplasms, somatic mutations of ATM occur frequently in mantle cell lymphomas (MCL), chronic lymphoblastic leukemia (CLL) and T-cell prolymphocytic
leukemia (TPLL).
Gene:
BCL2
Clinical Utility:
BCL2 mutations in follicular lymphoma correlate with activation-induced cytidine deaminase expression and frequently alter the amino acid sequence of the protein.Mutations in the BCL2 coding sequence at diagnosis are associated with shortened time to transformation and earlier death due to lymphoma.
Gene:
BIRC3
Clinical Utility:
BIRC3 is an important regulator of NF-kB signaling, and a recurrently mutated gene in Chronic lymphocytic leukemia (CLL). CLL patients with low BIRC3 expression experience a more rapid disease progression. BIRC3-mutated primary CLL cells are less sensitive to flu-darabine.
Gene:
BRAF
Clinical Utility:
Some mutations in BRAF predict response to RAF inhibitors in a variety of solid tumors. Therapies targeting BRAF V600-mutated melanoma (vemurafenib, dabrafenib, and trametinib) have been approved by the FDA. BRAF V600E is a negative prognostic marker in colorectal cancers, with resistance to anti-EGFR therapy in some clinical settings. In CNS neoplasms, BRAF V600E mutations are rarely found in adult gliomas
with only 1% to 2 % mutated samples in glioblastomas and 2% to 5% in low grade adult gliomas. Even though a clear prognostic difference could not be established yet, BRAF V600E mutant glioblastomas have some distinct histopathological and molecular features. BRAF mutations are in most instances mutually exclusive to canonical IDH mutations.
Gene:
BTK
Clinical Utility:
Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. BTK may predict response to BTK inhibitors.
Gene:
CARD11
Clinical Utility:
CARD11 functions as a key signaling scaffold that controls antigen-induced lymphocyte activation during the adaptive immune response. Somatic mutations in CARD11 are frequently found in Non-Hodgkin lymphoma, and at least three classes of germline CARD11 mutations have been described as the basis for primary immunodeficiency.
Gene:
CD79B
Clinical Utility:
Activating mutations in CD79 and MYD88 have recently been found in a subset of diffuse large B-cell lymphoma (DLBCL), identifying B-cell receptor and MYD88 signalling as potential therapeutic targets for personalized treatment.
Gene:
CDKN2A
Clinical Utility:
Loss of CDKN2A is common in lymphoid neoplasms, has prognostic implications in some malignancies, and presents a therapeutic target for CDK4/6 inhibitors.
Gene:
CXCR4
Clinical Utility:
Approximately 30% of patients with lymphoplasmacytic lymphoma (LPL) carry a mutation of the CXCR4 gene, resulting in diminished response to therapy with Bruton tyrosine kinase (BTK) inhibitors, as well as more aggressive disease.
Gene:
DNMT3A
Clinical Utility:
Mutations in DNMT3A have been associated with poor prognosis in subsets of MDS and AML, depending on the clinical and molecular context. Patients with DNMT3A-mutated AML have an inferior survival when treated with standard dose induction therapy and should be considered for high-dose induction therapy.
Gene:
EZH2
Clinical Utility:
EZH2 mutations correlate with adverse outcomes in myeloid disorders (MDS, CMML, PMF).
Gene:
IDH1
Clinical Utility:
IDH (IDH1 and IDH2) mutations are more prevalent in low grade diffuse gliomas and in secondary glioblastomas, they are associated with improved prognosis in low grade gliomas, and may predict response to therapy (IDH inhibitors, temolozomide). In acute myeloid leukemia (AML), somatic mutations in IDH1 and IDH2 are highly recurrent and are almost exclusively heterozygous and occur more frequently in
AML in normal cytogenetics.
Gene:
IDH2
Clinical Utility:
IDH (IDH1 and IDH2) mutations are more prevalent in low grade diffuse gliomas and in secondary glioblastomas, they are associated with improved prognosis in low grade gliomas, and may predict response to therapy (IDH inhibitors, temolozomide). In acute myeloid leukemia (AML), somatic mutations in IDH1 and IDH2 are highly recurrent and are almost exclusively heterozygous and occur more frequently in AML in normal cytogenetics.
Gene:
KMT2D
Clinical Utility:
Lysine (K)-specific methyltransferase 2D (KMT2D) is a gene that encodes a protein that functions as a histone methyltransferase that methylates the LYS-4 position of histone H3. KMT2D is altered in 8.52% of all cancers with lung adenocarcinoma, colon adenocarcinoma, bladder urothelial carcinoma, breast invasive ductal carcinoma, and endometrial endometrioid adenocarcinoma having the greatest prevalence of alterations. In follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), KMT2D has emerged as one of the most frequently mutated gene. KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell activating pathways.
Gene:
MAP2K1
Clinical Utility:
MAP2K1 mutations may confer resistance to BRAF and MEK inhibitors.
Gene:
MYD88
Clinical Utility:
MYD88 mutations may aid in differential diagnosis of DLBCL and LPL and may predict response to therapy (ibrutinib).
Gene:
NOTCH1
Clinical Utility:
NOTCH1 mutations may be associated with poor prognosis in a subset of NSCLC. NOTCH1 may contribute to TKI resistance in NSCLC. About 4-15% of Chronic lymphocytic leukemia (CLL) harbor mutations in NOTCH1. NOTCH1 mutations are more frequent in IGVH-unmutated cases nad been associated with disease progression. More specifically, NOTCH1 mutations have been found in up to 42% of trisomy 12 CLL cases.
Gene:
NOTCH2
Clinical Utility:
Recurrent gain-of-function mutations of NOTCH1 and NOTCH2 have been reported in lymphoproliferative disorders of the B series, including chronic lymphocytic leukemia (CLL), mantle cell (MCL), splenic marginal zone (SMZL), diffuse large B cell (DLBCL) and follicular (FL), Burkitt’s (BL) and Hodgkin’s (HL) lymphomas. Non-mutational mechanisms of NOTCH activation have also been reported in multiple myeloma.
Gene:
NRAS
Clinical Utility:
Mutations and overexpression of the neuroblastoma RAS viral (v‐ras) oncogene homolog (NRAS) are found across multiple tumor types and are common in highly metastatic cancers such as tumors of unknown primary, melanomas, and sarcomas that display a striking propensity for lung metastasis. Clinical studies suggest that patients with NRAS‐mutant or amplified tumors suffer from more aggressive disease
than patients with wild‐type NRAS alleles.NRAS mutations in mCRC are predictive of lack of benefit to anti-EGFR therapeutic agents (cetuximab, panitumumab), and may predict response to MEK inhibitors in metastatic melanoma.
Gene:
PLCG2
Clinical Utility:
Testing for PLCG2 mutations may be useful in patients receiving acalabrutinib and suspected of having progression.
Gene:
RHOA
Clinical Utility:
Somatic mutations in RHOA, DNMT3A, IDH2 and TET2 have been reported in angioimmunoblastic T cell lymphoma (AITL) and Peripheral T-cell Lymphoma not otherwise specified (PTCL-NOS), which are characterized by follicular helper T-cell phenotypes. RHOA mutations have been also identified in gastric cancer and Burkitt lymphoma.
Gene:
SF3B1
Clinical Utility:
SF3B1 mutations were significantly associated with ER-positive disease, AKT1 mutations, and distinct copy number alterations. Additional profiling of hotspot mutations in a panel of special histological subtypes of breast cancer showed that 16% and 6% of papillary and mucinous carcinomas of the breast harboured the SF3B1 K700E mutation. In uveal melanoma, SF3B1 mutations are generally associated with tumors having a favorable prognosis. In additon, SF3B1 R625 mutations in conjunction with GNAQ and GNA11 mutations are a genetic marker of malignancy in blue nevus-like melanocytic proliferations. In Chronic lymphocytic leukemia (CLL), SF3B1, a ubiquitously expressed splicing factor, has been found mutated in 5-17% of CLL cases, in which it is associated with a poor prognosis, reduced overall survival, and resistance to
treatment with fludarabine.
Gene:
STAT3
Clinical Utility:
STAT3 mutation testing is recommended under certain circumstances for diagnosis of Large granular lymphocyte leukemia (LGLL) and NK Leukemias. STAT3 mutations have been identified in approximately 50% of LGLL and NK Leukemia
Gene:
STAT5B
Clinical Utility:
The STAT5B gene is associated with autosomal recessive growth hormone insensitivity with immunodeficiency
Gene:
TET2
Clinical Utility:
TET2 is frequently deleted or mutated in myeloid malignancies, may have adverse prognostic impact in AML, and may be predictive of a response to hypomethylating agents in MDS.
Gene:
TP53
Clinical Utility:
Somatic TP53 mutations are generally associated with poor prognosis in myeloid neoplasms, and may modulate treatment response in low-risk MDS.
Gene:
BCL6
Clinical Utility:
Translocations affecting BCL6 gene frequently occur in activated B cell diffuse large B-cell lymphoma (ABC-DLBCL), which is a more aggressive form of DLBCL.
Gene:
JAK1
Clinical Utility:
Mutations in JAK1 and JAK3 have been observed in various lymphoid malignancies of T-cell and B-cell lineages as well in some acute myeloblastic leukemia.
Gene:
JAK3
Clinical Utility:
Mutations in JAK1 and JAK3 have been observed in various lymphoid malignancies of T-cell and B-cell lineages as well in some acute myeloblastic leukemia.
Gene:
SETD2
Clinical Utility:
SETD2 mutations were found in 12% of cases of B-cell acute lymphoblastic leukemia, 1% to 2% of cases of B-cell lymphoma, chronic lymphocytic leukemia, and AML, and occasionally cases of myeloproliferative neoplasm.
Gene:
TNFRSF14
Clinical Utility:
Mutational profile studies of follicular lymphoma (FL) patients now reveal a number of abnormalities mostly affecting chromatin remodeling proteins that are being explored for their suitability as FL therapeutic targets. Together with MLL2, EZH2, CREBBP, among other genes, mutations in TNFRSF14 gene, a member of the superfamily of TNF receptors, may be found in follicular lymphoma samples.