Oncogenes/Tumor Suppressor Genes

Oncogenes: Gain of function mutation converts a proto-oncogene (normal gene) to oncogene → increases cancer risk. Requires damage to only one allele of a proto-oncogene.

ALK (Receptor tyrosine Kinase):

  • Lung Adenocarcinoma (Adenocarcinoma of the Lung Kinase)

EGRF (ERBB1) (Receptor tyrosine kinase):

  • Lung Adenocarcinoma

HER2(ERBB2) (Receptor tyrosine kinase):

  • Breast carcinoma

  • Gastric carcinoma

RET (Receptor tyrosine kinase):

  • MEN2A and 2B

  • Medullary and Papillary thyroid carcinoma

  • Phaeochromocytoma

BCR-ABL (Non-receptor tyrosine kinase):

  • CML

  • ALL

JAK2 (Non-receptor tyrosine kinase):

  • Myeloproliferative neoplasms

BRAF (Serine/threonine kinase):

  • Melanoma

  • Non-Hodgkin lymphoma

  • Papillary thyroid carcinoma

  • Hairy cell leukemia

c-KIT (CytoKIne receptor CD117):

  • Gastrointestinal stromal tumor (GIST)

  • Mastocytosis

MYCC (c-myc) (Transcription factor):

  • Burkitt Lymphoma

MYCN (N-myc) (Transcription factor):

  • Neuroblastoma

MYCL1 (Transcription factor):

  • Lung tumor (small cell)

KRAS (RAS GTPase): KRAS mutation prevents conversion of GTP to GDP (due to abnormal GTPase function) a constant activation KRAS àMAPK pathway an uncontrolled cellular proliferation.

  • Colorectal cancer

  • Lung cancer

  • Pancreatic cancer

BCL-2 (Anti-apoptotic molecule -inhibits apoptosis):

  • Follicular and diffuse large B Cell Lymphomas

Tumor suppressor genes: Loss of function → increaes cancer risk. Both (two) alleles of tumor suppersor gene must be lost for expression of disease.

APC: Negative regulator of b-catenin/WNT pathway. Mutation of the APC tumor suppressor gene is the first step in the classic adenoma-to-carcinoma sequence. The microsatellite instability pathway is characterized by mutations in DNA mismatch repair genes and is implicated in the development of hereditary nonpolyposis colorectal cancer (Lynch syndrome).

  • Colorectal cancer (associated with FAP)

BRCA1/BRCA2: DNA repair protein. BRCA1 and BRCA2 produce tumor suppression proteins involved in repair of double-stranded DNA breaks via homologous recombination repair. Loss of function in a pair of BRCA alleles leads to the accumulation of unrepaired genomic mutations, which dramatically increases the risk of oncogenesis.  Although BRCA defects are inherited in an autosomal dominant fashion, cancer occurs only after a somatic mutation strikes the complementary BRCA allele.  Repair of DNA cross-links typically involves inducing double-stranded DNA breaks, therefore, proteins encoded by BRCA genes are also important for cross-link repair.  Tumor cells with BRCA mutations are more likely to accumulate excessive DNA cross-links and undergo apoptosis when exposed to platinum compounds, resulting in greater tumor regression compared to patients with intact BRCA genes.

  • Breast cancer

  • Ovarian cancer

  • Pancreatic cancer

CDKN2A (Cyclin Dependent Kinase): p16, blocks G1à S phase 

  •  Melanoma

  • Lung cancer

  • Pancreatic caner

DCC:

  • Colorectal cancer

SMAD4 (DPC4):

  • Pancreatic cancer

  • Colorectal cancer

MEN1: Menin.

  • Multiple Endocrine Neoplasia 1

NF1 (Chr 17): Neurofibromin (Ras GTPase activating protein).

  • Neurofibromatosis type 1

NF2: Merlin (schwannomin) protein.

  • Neurofibromatosis type 2

PTEN: Negative regulator of P13k/AKT pathway.

  • Prostate cancer

  • Breast cancer

  • Endometrial cancer

RB1: Inhibits E2F. Blocks G1à S phase transition until cell ready to divide. Binds and inhibits E2F transcription factors → halting cell cycle at G1/S checkpoint. In contrast, when cell ready to divide:  Rb protein phosphorylated by cyclin-dependent kinases. Allows cell to proceed through G1/S checkpoint. Loss of function of Rb: Unrestricted progression through G1/S checkpoint → uncontrolled cell division.

  • Retinoblastoma

  • Osteosarcoma

TP53: p53, activates p21. Blocks G1à S phase (causes cell cycle arrest) if DNA damage detected. Initiates cell apoptosis if DNA repair fails.

  • Acquired p53 mutations found in majority of spontaneous cancers. Final mutation in the adenoma-carcinoma sequence.

  •  Inherited p53 mutation → Li-Fraumeni syndrome: Multiple malignancies at an early age: Sarcoma, Breast/Brain, Lung/Leukemia, Adrenal gland

TSC1: Hamartin protein

  • Tuberous sclerosis

TSC2: Tuberin protein

  • Tuberous sclerosis

VHL: Inhibits hypoxia-inducible factor 1a

  • Von Hippel-Lindau disease:

  • High risk of bilateral renal cell carcinomas, cerebellar hemangioblastomas, retinal hemangiomas, liver cysts

WT1: Transcription factor that regulates urogenital development

  • Wilms Tumor (nephroblastoma)