VHL

VHL (von Hippel-Lindau tumor suppressor) is part of an E3 ubiquitin protein ligase complex, which promotes degradation of HIF-alpha. Simple variants in VHL are seen in about 6% of all tumors, including 36% of kidney tumors, where they are diagnostic for clear cell renal cell carcinoma. VHL contributes to von Hippel-Lindau disease and sporadic tumors, including clear cell renal carcinoma. VHL-mutant tumors may be responsive to mTOR and VEGFR inhibitors.

STK11

STK11 (LKB1)(serine/threonine kinase 11) is a tumor suppressor, which regulates the activity of AMPK family members. Simple variants in STK11 are seen in about 1% of all tumors, including 5% of lung tumors and up to 20% of gastrointestinals tumors. Germline variants in STK11 cause the Peutz-Jeghers Syndrome. STK11 variants may predict response to inhibitors of the mTOR pathway.

TP53

TP53 encodes the transcription factor Tp53, which is a tumor suppressor involved in cell cycle arrest and apoptosis, and is the most frequently mutated gene in cancer. Simple variants in TP53 are seen in about 33% of all tumors. Germline variants in TP53 cause the Li-Fraumeni Syndrome. Mutations in TP53 have been implicated in chemoresistance.

SRC

SRC (proto-oncogene tyrosine-protein kinase Src) is a member of multiple signaling pathways and activation and/or overexpression has been observed in many cancers. Simple variants in SRC are seen in about 0.3% of all tumors, including 3% of skin tumors and 2-3% of gastrointestinal tumors. SRC activiation may predict response to SRC inhibitors currently in clinical development.

SMARCB1

SMARCB1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) is a member of the SWI/SNF chromatin remodeling complex and regulates transcription of several genes involved in cell proliferation. Simple variants in SMARCB1 are seen in about 2% of all tumors, including about 20% of soft tissue tumors and 7% of central nervous system tumors. SMARCB1 inactivation is characteristic of atypical teratoid/rhabdoid tumors. SMARCB1 inactivation may predict response to EZH2 inhibitors.

SMO

SMO (smoothened, frizzled class receptor) is a G-protein coupled receptor and member of the Hedgehog signaling pathway, which is involved in cell fate, proliferation, and survival. Simple variants in SMO are seen in about 1% of all tumors, including 3% of skin and colorectal tumors. SMO gain-of-function mutations are associated with basal cell carcinoma. SMO variants may predict resistance to certain HH-pathway inhibitors in basal cell carcinoma.

RET

RET (proto-oncogene tyrosine-protein kinase receptor Ret) activates the MAPK pathway for cell proliferation and the PI3K/AKT pathway for cell survival. Simple variants in RET are seen in about 3% of all tumors, including 25% of thyroid tumors. Germline RET variants are diagnostic for multiple endocrine neoplasia and familial medullary thyroid carcinoma. RET-activating mutations and rearrangements are common in medullary thyroid cancer. RET variants predict responses to kinase inhibitors.

SMAD4

SMAD4 mediates the transcriptional response to TGF-beta and loss of SMAD4 has been implicated in several cancers. Simple variants in SMAD4 are found in about 3% of all tumors, including up to 50% of gastrointestinal tumors (intestine and pancreas). Mutations in SMAD4 are involved in several hereditary syndromes with cancer predisposition, including juvenile polyposis syndrome and hemorrhagic hereditary telangiectasia (HHT) syndrome. SMAD4 loss is associated with a worse prognosis in colorectal and pancreatic carcinomas.

RB1

RB1 (retinoblastoma 1) is a key negative regulator of the G1 to S transition during cell division. Simple variants in RB1 are seen in about 3% of all tumors, including all retinoblastomas and ~10% of soft tissue and urinary tract tumors. Germline variants in RB1 may diagnose the retinoblastoma syndrome. Inactivation of RB1 and loss of RB1 tumor suppressor function has been identified in many early stage cancers.

PTEN

PTEN (phosphatase and tensin homolog) is a tumor suppressor with roles in the cell cycle, growth, DNA repair, cell survival and regulation of the AKT-mTOR pathway. Simple variants in PTEN are seen in about 6% of all tumors, including 39% of endometrial tumors, 13% of central nervous system tumors, 8.5% of skin tumors, and 7% of prostate and breast tumors. PI3K inhibitors have shown antitumor activity in preclinical studies of PTEN-deficient breast and prostate cancer, but not in a study of endometrial cancer.