18.6 Cancer Genetics

Cancer Genetics

Cancer is fundamentally a genetic disease of somatic cells, although about 5–10% of cases carry a strong inherited predisposition. PA-CAT Bulletin of Information, rev. 20240815, Table 8, lists Cancer as part of Medical Genetics and Cancer. The 26-item genetics block commonly tests gene categories, cell-cycle checkpoints, apoptosis, and hereditary syndromes.

Gene Categories

Three categories of cancer genes differ in how mutation changes their function:

Knudson's two-hit hypothesis applies to tumor suppressors: both alleles must be inactivated. In familial cases the first hit is inherited (germline) and the second is somatic, so tumors appear earlier and bilaterally. In sporadic cases both hits are somatic, so disease appears later and is usually unilateral. Retinoblastoma is the classic example.

Cell Cycle Checkpoints

The cell cycle (G1 → S → G2 → M) is governed by cyclins and cyclin-dependent kinases (CDKs). Key checkpoints:

• G1/S (restriction point) — controlled by the p16–cyclin D–CDK4/6–Rb–E2F axis. Rb (retinoblastoma protein) holds E2F inactive until phosphorylated by cyclin D–CDK4/6. p53 mediates G1 arrest after DNA damage by inducing p21, which inhibits CDKs and blocks S-phase entry.
• G2/M — governed by CDK1–cyclin B; verifies DNA replication completion and detects damage.
• Spindle assembly checkpoint (M) — ensures all chromosomes are properly attached to spindle microtubules before anaphase.

p53, called the guardian of the genome, is mutated in roughly 50% of all cancers. Loss of p53 disables DNA-damage-induced arrest and apoptosis, allowing damaged cells to divide.

Apoptosis

Apoptosis (programmed cell death) eliminates damaged or surplus cells. The intrinsic (mitochondrial) pathway: DNA damage → p53 → up-regulation of pro-apoptotic BAX and down-regulation of anti-apoptotic BCL-2 → mitochondrial outer-membrane permeabilization → cytochrome c release → caspase cascade (initiator caspase-9 → executioner caspases-3/6/7). The extrinsic pathway: death receptors (Fas, TNF receptor) → caspase-8 → executioner caspases. Evasion of apoptosis is a hallmark of cancer; for example, BCL-2 overexpression from the t(14;18) translocation in follicular lymphoma blocks apoptosis and allows neoplastic B cells to accumulate.

Hallmarks of Cancer (Hanahan & Weinberg)

1. Sustained proliferative signaling (e.g., oncogenic RAS, growth-factor autocrine loops).
2. Evade growth suppressors (loss of RB1, TP53).
3. Resist apoptosis (e.g., BCL-2 overexpression).
4. Enable replicative immortality via telomerase reactivation.
5. Induce angiogenesis (VEGF, FGF signaling).
6. Activate invasion and metastasis (EMT, matrix metalloproteinases).
7. Deregulate cellular energetics (Warburg effect — aerobic glycolysis).
8. Avoid immune destruction (PD-L1 expression, MHC downregulation).
9. Genome instability and mutation (repair defects, mutator phenotype).
10. Tumor-promoting inflammation (tumor-associated macrophages, cytokines).

Hereditary Cancer Syndromes

Lynch syndrome is a mutator phenotype — loss of mismatch repair produces microsatellite instability (MSI), detectable by PCR or immunohistochemistry, and guides immunotherapy selection. FAP follows the adenoma–carcinoma sequence: an inherited APC allele plus somatic loss of the other allele initiates polyp formation; additional mutations in KRAS, TP53, and others drive progression to carcinoma.

Tumor Heterogeneity and Evolution

Cancers evolve by clonal expansion and Darwinian selection: successive rounds of mutation yield subclones with different growth advantages, and therapy selects resistant clones. Driver mutations (in oncogenes and tumor suppressors) confer growth advantage, whereas passenger mutations are neutral byproducts of genomic instability. Intratumor heterogeneity — distinct subclones within one tumor — complicates treatment and drives resistance, which is why combination therapy targeting multiple pathways is often more durable than single-agent treatment.

Key Oncogenes and Tumor Suppressors: Gene-to-Cancer Map

Building on the category table above, the following pairings are high-yield because PA-CAT items commonly name a cancer and ask for the mutated gene, or vice versa. Memorize the gene, its class, and the signature cancer.

Notice the asymmetry: oncogenes are activated by gain-of-function (amplification, point mutation, translocation to an active enhancer), whereas tumor suppressors are inactivated by loss-of-function (deletion, nonsense, frameshift). A useful PA-CAT shortcut: if the question names a translocation producing a fusion gene or constitutive activation (BCR-ABL, MYC-IgH, BCL2-IgH), think oncogene; if it describes loss of both alleles or a familial syndrome with bilateral tumors, think tumor suppressor.