Carcinogenesis & Molecular Oncology
Pathology · Neoplasia · lean revision notes
Carcinogenesis & Molecular Oncology
Cancer is fundamentally a genetic disease of somatic cells — a stepwise accumulation of mutations that liberate a clone from normal growth controls. This topic is dense, high-yield, and reliably tested in NEET PG through gene–tumour associations, viral oncogenesis, and the molecular hallmarks of cancer.
Core principle: cancer is a multistep, monoclonal genetic disease
Four classes of regulatory genes are the principal targets of cancer-causing mutations:
- Proto-oncogenes → growth-promoting; gain-of-function (dominant) → become oncogenes.
- Tumour suppressor genes (TSGs) → growth-inhibiting; loss-of-function (recessive at cell level) → both alleles must be lost (two-hit hypothesis).
- Genes regulating apoptosis → can act either way (e.g. BCL2 anti-apoptotic, BAX pro-apoptotic).
- DNA repair genes → "caretaker" genes; their loss produces a mutator phenotype.
High-yield: A single oncogene activation is not enough to cause cancer. Carcinogenesis requires accumulation of multiple driver mutations (multistep model). Oncogenes are dominant (one mutant allele suffices); classic TSGs are recessive (need two hits) — though some show haploinsufficiency.
The Hallmarks of Cancer (Hanahan & Weinberg)
High-yield: Eight hallmarks + two enabling characteristics.
- Self-sufficiency in growth signals
- Insensitivity to growth-inhibitory signals
- Evasion of apoptosis
- Limitless replicative potential (telomerase)
- Sustained angiogenesis
- Invasion & metastasis
- Reprogramming of energy metabolism (Warburg effect — aerobic glycolysis)
- Evasion of immune destruction
Enabling characteristics: genomic instability & mutation; tumour-promoting inflammation.
Proto-oncogenes and oncogenes
Proto-oncogenes encode normal components of growth-signalling pathways: growth factors, growth-factor receptors, signal transducers, transcription factors, and cell-cycle regulators. Activation mechanisms:
- Point mutation (e.g. RAS)
- Gene amplification (e.g. N-MYC, HER2/NEU)
- Chromosomal translocation (e.g. ABL, MYC, BCL2)
| Oncogene | Function/class | Activation | Associated tumour |
|---|---|---|---|
| RAS (K, H, N) | GTPase signal transducer | Point mutation | Most common oncogene in human cancer — pancreatic (~90% K-RAS), colon, lung, AML |
| MYC | Nuclear transcription factor | Translocation t(8;14) | Burkitt lymphoma |
| N-MYC | Transcription factor | Amplification | Neuroblastoma (poor prognosis) |
| L-MYC | Transcription factor | Amplification | Small cell lung carcinoma |
| HER2/NEU (ERBB2) | Tyrosine kinase receptor (EGFR family) | Amplification | Breast, gastric — target of trastuzumab |
| ABL | Non-receptor tyrosine kinase | t(9;22) BCR-ABL | CML, ALL — target of imatinib |
| RET | Receptor tyrosine kinase | Point mutation | MEN 2A/2B, medullary thyroid Ca |
| KIT (CD117) | Receptor tyrosine kinase | Mutation | GIST — target of imatinib |
| BCL2 | Anti-apoptotic | t(14;18) | Follicular lymphoma |
| CYCLIN D1 (CCND1) | Cell cycle G1→S | t(11;14) | Mantle cell lymphoma |
| CDK4 / Cyclin D | Cell cycle kinase | Amplification | Melanoma, sarcoma |
| EGFR | Receptor tyrosine kinase | Mutation/amplification | Lung adenocarcinoma — gefitinib/erlotinib |
| BRAF (V600E) | Serine/threonine kinase | Point mutation | Melanoma, hairy cell leukaemia, papillary thyroid Ca, colorectal Ca |
High-yield: RAS is the single most commonly mutated oncogene in human cancers. The mutation locks RAS in the active GTP-bound state because it abolishes its intrinsic GTPase activity (cannot hydrolyse GTP → GDP) → continuous downstream MAPK and PI3K signalling.
Signal flow (RTK pathway): Growth factor → receptor tyrosine kinase → RAS-GTP → RAF → MEK → ERK (MAPK) → nuclear transcription → cyclin D/CDK4 → phosphorylates RB → cell enters S phase.
Mnemonic — RAS partners: RAS activation downstream involves the MAPK cascade (RAS → RAF → MEK → MAPK/ERK).
Tumour suppressor genes
These genes normally apply brakes to proliferation. Knudson's two-hit hypothesis (derived from retinoblastoma) states that both alleles must be inactivated. In familial/hereditary cancers, one defective allele is inherited (germline) → only one more "hit" needed → earlier, often bilateral/multifocal tumours. In sporadic cancers, both hits are somatic.
| TSG | Chromosome | Normal function | Syndrome / tumours |
|---|---|---|---|
| RB | 13q14 | Gatekeeper of G1→S checkpoint | Retinoblastoma, osteosarcoma |
| TP53 (p53) | 17p13 | "Guardian of the genome" | Li-Fraumeni syndrome; >50% of all cancers |
| APC | 5q21 | WNT/β-catenin regulation | FAP, colorectal Ca |
| BRCA1 | 17q21 | DNA repair (HR) | Breast, ovarian Ca |
| BRCA2 | 13q12 | DNA repair (HR) | Breast (incl. male), ovarian, pancreatic |
| NF1 | 17q11 | Neurofibromin (RAS-GAP) | Neurofibromatosis type 1 |
| NF2 | 22q12 | Merlin | NF2 — bilateral acoustic schwannomas/meningiomas |
| VHL | 3p25 | Degrades HIF | Renal cell Ca (clear cell), haemangioblastoma, phaeochromocytoma |
| WT1 | 11p13 | Transcription factor | Wilms tumour |
| PTEN | 10q23 | Phosphatase, inhibits PI3K/AKT | Cowden syndrome, endometrial, prostate Ca |
| CDKN2A (p16) | 9p21 | CDK4 inhibitor | Melanoma, pancreatic Ca |
| TSC1/TSC2 | 9q/16p | Inhibits mTOR | Tuberous sclerosis |
| STK11/LKB1 | 19p13 | Kinase | Peutz-Jeghers syndrome |
| MEN1 | 11q13 | Menin | MEN type 1 |
| SMAD4 (DPC4) | 18q21 | TGF-β signalling | Pancreatic, colon Ca |
RB — the master cell-cycle gatekeeper
RB controls the G1→S restriction point. In its hypophosphorylated (active) form, RB binds and sequesters E2F, blocking S-phase entry. Mitogenic signals → cyclin D/CDK4-6 → phosphorylate RB → releases E2F → cell proliferates.
High-yield: Hypophosphorylated RB = active (brake ON). Loss of RB, cyclin D amplification, CDK4 amplification, p16 (CDKN2A) loss, or HPV E7 binding all converge to release E2F → unchecked proliferation. This is why many cancers disrupt the RB pathway.
p53 — the guardian of the genome
p53 is the most commonly mutated gene in human cancer. On DNA damage, ATM/ATR-mediated signalling stabilises p53 (normally degraded by MDM2). Activated p53 produces:
- G1 arrest via transcription of p21 (CDK inhibitor).
- DNA repair (e.g. GADD45) — "pause and repair".
- Apoptosis (via BAX, PUMA, NOXA) if damage is irreparable.
p53 flow: DNA damage → ATM/ATR → p53 stabilised (MDM2 released) → p21 ↑ → CDK inhibition → G1 arrest → repair → if repaired, resume; if not repaired → BAX/PUMA → apoptosis.
High-yield: Li-Fraumeni syndrome = germline TP53 mutation → markedly increased risk of sarcomas, breast Ca, brain tumours, leukaemia, adrenocortical Ca (the "SBLA" complex), often in childhood/young adulthood. HPV E6 degrades p53.
APC–K-RAS–p53: the colorectal adenoma-carcinoma sequence
The classic Fearon-Vogelstein multistep model is a guaranteed exam favourite.
Normal epithelium → (loss of APC — 5q) → hyperproliferative/at-risk epithelium → (DNA hypomethylation) → early adenoma → (K-RAS mutation — 12p) → intermediate adenoma → (loss of SMAD2/4 / DCC — 18q) → late adenoma → (loss of p53 — 17p) → carcinoma → (other mutations) → invasion/metastasis.
- APC loss is the earliest and initiating event in the classic (chromosomal instability) pathway. APC normally promotes β-catenin degradation; loss → β-catenin accumulates → drives WNT-target genes (MYC, cyclin D1).
- The second major colorectal pathway is the microsatellite instability (MSI) pathway via defective DNA mismatch repair (Lynch syndrome).
| Feature | Chromosomal instability (CIN) | Microsatellite instability (MSI) |
|---|---|---|
| Initiating defect | APC loss | Mismatch repair (MMR) genes |
| Genes | APC, K-RAS, p53, SMAD4/DCC | MSH2, MLH1, MSH6, PMS2 |
| Syndrome | FAP | Lynch (HNPCC) |
| Location | Left colon | Right colon |
| Histology | Usual | Mucinous, signet-ring, lymphocytic |
| Prognosis | Worse | Better; predicts immunotherapy response |
DNA repair gene defects (caretaker genes)
These do not cause cancer directly but produce a mutator phenotype that accelerates mutation of oncogenes/TSGs. Mostly autosomal recessive inherited cancer syndromes.
| Defective repair | Syndrome | Clinical clues |
|---|---|---|
| Nucleotide excision repair (NER) | Xeroderma pigmentosum | UV sensitivity, skin cancers (BCC, SCC, melanoma) |
| Mismatch repair (MMR) | Lynch (HNPCC) | Colon, endometrial, ovarian Ca; MSI |
| Homologous recombination | BRCA1/2; Fanconi anaemia | Breast/ovarian; Fanconi → AML, pancytopenia, radial defects |
| Helicase (BLM) | Bloom syndrome | Sister chromatid exchanges, leukaemia/lymphoma |
| ATM kinase | Ataxia-telangiectasia | Cerebellar ataxia, telangiectasia, IgA deficiency, lymphoma, radiosensitivity |
| WRN helicase | Werner syndrome | Premature ageing |
High-yield: BRCA1/2 mutations create defective homologous recombination → exploited therapeutically by PARP inhibitors (olaparib) via synthetic lethality. Xeroderma pigmentosum = defective NER, autosomal recessive, extreme UV photosensitivity.
Apoptosis evasion and replicative immortality
- BCL2 (anti-apoptotic) overexpression via t(14;18) prevents cytochrome-c release → follicular lymphoma cells accumulate (slow-growing because they don't die, not because they divide fast).
- Telomerase reactivation gives "limitless replicative potential." Normal somatic cells shorten telomeres each division → replicative senescence. ~85–90% of cancers reactivate telomerase to maintain telomeres → immortality.
High-yield: Follicular lymphoma — t(14;18) → BCL2 (anti-apoptotic) overexpressed. Burkitt lymphoma — t(8;14) → c-MYC. CML — t(9;22) → BCR-ABL (Philadelphia chromosome).
Chemical carcinogenesis
Two stages: initiation (permanent DNA mutation by a carcinogen; irreversible) → promotion (proliferation of initiated cells; reversible, non-mutagenic, requires repeated exposure). Initiation must precede promotion.
Carcinogens are direct-acting or indirect (procarcinogens) requiring metabolic activation (often by cytochrome P-450).
| Agent | Type | Cancer |
|---|---|---|
| Aflatoxin B1 (Aspergillus) | Indirect | Hepatocellular Ca (p53 codon 249 mutation) |
| Vinyl chloride | Indirect | Hepatic angiosarcoma |
| Benzene | — | AML |
| Benzo(a)pyrene (smoke) | Indirect | Lung, bladder Ca |
| β-naphthylamine / aniline dyes | Indirect | Bladder (transitional cell) Ca |
| Arsenic | — | Skin, lung, angiosarcoma |
| Asbestos | — | Mesothelioma, lung Ca (synergy with smoking) |
| Nitrosamines | Indirect | Gastric Ca |
| Alkylating agents (cyclophosphamide) | Direct | AML, bladder Ca |
| Diethylstilbestrol (DES) | Hormonal | Vaginal clear cell adenocarcinoma (in daughters) |
High-yield: Aflatoxin B1 → HCC via a signature G→T transversion at codon 249 of p53. Vinyl chloride → hepatic angiosarcoma. Aniline dyes (β-naphthylamine) → bladder cancer.
Radiation carcinogenesis
- UV light (UVB) → pyrimidine dimers → skin cancers (BCC most common, SCC, melanoma).
- Ionising radiation → most common radiation-induced malignancy is leukaemia (except CLL), then thyroid (especially in children), breast, lung. Latency varies.
Viral and microbial oncogenesis
A perennial NEET PG hotspot.
| Virus | Genome | Associated cancer | Mechanism |
|---|---|---|---|
| HPV (16, 18) | DNA | Cervical, anal, oropharyngeal SCC | E6 → degrades p53; E7 → inactivates RB |
| EBV | DNA | Burkitt lymphoma, nasopharyngeal Ca, Hodgkin, CNS lymphoma (HIV), gastric Ca | LMP-1 mimics CD40 |
| HBV / HCV | DNA / RNA | Hepatocellular carcinoma | Chronic inflammation, regeneration; HBx |
| HTLV-1 | RNA (retrovirus) | Adult T-cell leukaemia/lymphoma | Tax protein |
| HHV-8 (KSHV) | DNA | Kaposi sarcoma, primary effusion lymphoma | — |
| Merkel cell polyomavirus | DNA | Merkel cell carcinoma | — |
| H. pylori (bacterium) | — | Gastric adenocarcinoma, gastric MALT lymphoma | Chronic gastritis, CagA |
High-yield: HPV E6 → p53 degradation; E7 → RB inactivation — the single most tested mechanism in viral oncogenesis. HTLV-1 → adult T-cell leukaemia via the Tax gene. H. pylori is the only bacterium causing cancer (gastric Ca + MALT lymphoma) — early MALT lymphoma can regress with eradication therapy.
Mnemonic — DNA tumour viruses: "HHH-EM-K" → HPV, HBV, HHV-8, EBV, Merkel polyomavirus, KSHV. The only major RNA oncoviruses tested are HTLV-1 and HCV.
Tumour progression, invasion & metastasis
- Loss of E-cadherin → loss of cell-cell adhesion (e.g. lobular breast Ca, diffuse gastric Ca / CDH1 mutation) — a key step in epithelial-mesenchymal transition (EMT).
- Degradation of basement membrane by matrix metalloproteinases (MMPs).
- Angiogenesis driven by VEGF (target of bevacizumab); promoted by loss of p53/VHL (HIF accumulation) and hypoxia.
High-yield: VHL loss → HIF-1α not degraded → ↑VEGF → vascular tumours (clear cell RCC, haemangioblastoma). E-cadherin loss → invasion/metastasis.
Recently asked / exam angle
- Gene–tumour matching: RB → retinoblastoma + osteosarcoma; WT1 → Wilms; NF1 → neurofibromatosis; APC → FAP. These are repeatedly asked as single-best-answer matches.
- "Most common oncogene mutated" → RAS. "Guardian of the genome" → p53. "Gatekeeper gene" → RB; "caretaker genes" → DNA repair genes.
- Translocations: t(9;22) BCR-ABL (CML), t(8;14) c-MYC (Burkitt), t(14;18) BCL2 (follicular), t(15;17) PML-RARA (APL — responds to ATRA), t(11;14) cyclin D1 (mantle cell).
- Viral mechanisms: HPV E6/E7, HTLV-1 Tax, aflatoxin codon 249 p53.
- Li-Fraumeni (TP53), Lynch (MMR/MSI), FAP (APC), MEN 2 (RET) — syndrome-gene pairs.
- Two-hit hypothesis numericals and the adenoma-carcinoma sequence ordering (APC first, p53 last).
- Warburg effect (aerobic glycolysis) and PARP inhibitor synthetic lethality in BRCA tumours — newer molecular MCQs.
- Targeted therapy pairings: imatinib (BCR-ABL/KIT), trastuzumab (HER2), gefitinib (EGFR), rituximab (CD20), bevacizumab (VEGF).
Rapid revision
- RAS is the most commonly mutated oncogene; mutation abolishes GTPase activity → stuck in active GTP-bound state.
- p53 (17p) is the most commonly mutated gene overall; germline loss = Li-Fraumeni; acts via p21 → G1 arrest and BAX → apoptosis.
- RB (13q) guards G1→S; hypophosphorylated RB is active and sequesters E2F.
- Knudson two-hit hypothesis explains TSGs (recessive); oncogenes are dominant.
- APC loss is the earliest event in the colorectal adenoma-carcinoma sequence; p53 loss is late.
- HPV E6 degrades p53; E7 inactivates RB — cervical cancer.
- t(8;14) MYC = Burkitt; t(14;18) BCL2 = follicular; t(9;22) BCR-ABL = CML.
- N-MYC amplification = neuroblastoma (poor prognosis); HER2 amplification = breast Ca (trastuzumab).
- Aflatoxin B1 → HCC, p53 codon 249; vinyl chloride → hepatic angiosarcoma; aniline dyes → bladder Ca.
- Xeroderma pigmentosum = defective NER; Lynch = defective MMR/MSI; BRCA1/2 = defective homologous recombination (PARP-inhibitor sensitive).
- HTLV-1 (Tax) = adult T-cell leukaemia; H. pylori = gastric Ca + MALT lymphoma; EBV = Burkitt + nasopharyngeal Ca.
- Telomerase reactivation gives limitless replicative potential; Warburg effect = aerobic glycolysis; VHL loss → ↑VEGF.