Oncogenes & Tumor Suppressors

Two ways to lose growth control

Oncogenes. Proto-oncogenes are normal genes that promote growth (growth factors, receptors, signal transducers, transcription factors, cell-cycle proteins). A gain-of-function change turns one into an oncogene. Because the product is overactive, one mutated allele is enough: oncogenes act dominantly, like an accelerator stuck down.

Tumor suppressors. These genes brake the cell cycle, repair DNA, or trigger apoptosis. Cancer requires loss of function of both alleles, so they are recessive at the cellular level ("brakes cut"). Yet the inherited syndromes they cause are autosomal dominant, because a second hit somewhere in the body is nearly certain.

How proto-oncogenes are activated. Point mutation (RAS, BRAF V600E); gene amplification (HER2, N-MYC); or translocation that either creates a fusion kinase (BCR-ABL) or parks a gene under a strong promoter (c-MYC beside the immunoglobulin heavy-chain promoter).

Knudson's two-hit hypothesis. Worked out from retinoblastoma. In hereditary cases every cell already carries one defective allele (germline first hit), so a single somatic second hit completes the job: tumors are early and bilateral. In sporadic cases both hits must strike the same cell somatically, a rarer event: tumors are unilateral and later. The second hit is often loss of heterozygosity. The same logic applies to Li-Fraumeni syndrome and FAP.

Oncogenes and their cancers

RAS. A small GTPase that relays signals from growth-factor receptors down the MAP kinase cascade. Point mutations lock it in the active GTP-bound state (it cannot hydrolyze GTP), so proliferation never switches off. KRAS is mutated in colon, pancreatic, and lung cancers.

MYC family. Transcription factors that drive proliferation. In Burkitt lymphoma, t(8;14) moves c-MYC beside the heavy-chain (IgH) promoter: "starry-sky" histology, EBV association, and an endemic jaw mass. N-MYC amplification in neuroblastoma signals a poor prognosis; L-MYC is linked to small cell lung cancer.

HER2/neu (ERBB2). An EGF-receptor-family tyrosine kinase amplified in ~20% of breast cancers and in gastric cancer. It predicts aggressive disease and is the target of trastuzumab.

BCR-ABL. The Philadelphia chromosome, t(9;22), fuses BCR and ABL into a constitutively active tyrosine kinase. It defines CML (>90% of cases), occurs in some ALL, and is inhibited by imatinib.

RET. A receptor tyrosine kinase. Germline activating mutations cause MEN 2A (medullary thyroid carcinoma, pheochromocytoma, parathyroid hyperplasia), MEN 2B (medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas, marfanoid habitus), and familial medullary thyroid carcinoma, so carriers undergo prophylactic thyroidectomy. Somatic RET rearrangements occur in papillary thyroid carcinoma.

Cell-cycle gatekeepers: TP53 and RB

TP53, guardian of the genome. On chromosome 17p. After DNA damage, p53 induces p21, a CDK inhibitor that halts the cycle at G1/S; it then triggers DNA repair or, if damage is irreparable, apoptosis by upregulating BAX. TP53 is mutated in >50% of human cancers, the most of any gene. MDM2 normally degrades p53, and HPV E6 targets it for destruction. Germline loss causes Li-Fraumeni syndrome: sarcoma, breast cancer, leukemia, and adrenocortical carcinoma at young ages across generations.

RB, the G1/S brake. On chromosome 13q14. Hypophosphorylated RB binds E2F and blocks the G1→S transition. Growth signals activate cyclin D–CDK4/6, which phosphorylates RB and releases E2F to transcribe S-phase genes. Loss of RB leaves E2F unopposed. Germline RB mutation causes retinoblastoma (leukocoria, a "white pupil") and later osteosarcoma. HPV E7 binds and inactivates RB.

Other tumor suppressors and their syndromes

APC. On 5q; part of the complex that degrades β-catenin in Wnt signaling, so its loss lets β-catenin accumulate and drive transcription. APC loss is the first mutation in the colorectal adenoma-carcinoma sequence (APC → KRAS → TP53, with loss of SMAD4/DCC on 18q along the way). Germline loss causes familial adenomatous polyposis: thousands of polyps and ~100% colorectal cancer risk without colectomy.

BRCA1 and BRCA2. On 17q and 13q; both repair DNA double-strand breaks by homologous recombination. Loss raises breast and ovarian cancer risk; BRCA2 also raises male breast, pancreatic, and prostate cancer. PARP inhibitors (e.g., olaparib) exploit this: blocking PARP-driven repair leaves recombination-deficient tumor cells unable to fix the resulting breaks (synthetic lethality).

VHL, NF1, WT1. VHL (3p) normally targets HIF-1α for degradation; its loss lets HIF-1α accumulate, boosting VEGF and EPO, which explains vascular tumors and polycythemia. NF1 (17q) encodes neurofibromin, a RAS-GAP that switches RAS off; loss causes neurofibromatosis type 1. WT1 (11p) loss causes Wilms tumor (nephroblastoma).

Bilateral retinoblastoma followed by osteosarcoma = germline RB. Sarcoma plus early breast cancer, leukemia, and adrenocortical carcinoma in one family = germline TP53. Medullary thyroid carcinoma plus pheochromocytoma = activating RET, an inherited oncogene (unusual, since most familial cancer genes are tumor suppressors).