Pathology chapters
Carcinogenesis and carcinogenic agents
How normal cells become cancer cells: the genes involved (oncogenes, tumour suppressor genes, DNA repair and apoptosis genes), the hallmarks of cancer, the multistep model, and the chemical, radiation and viral carcinogens that matter for the exam and in Pakistan.
- Cancer results from accumulated mutations in four classes of normal regulatory genes: growth-promoting proto-oncogenes (gain of function, one allele enough), tumour suppressor genes (loss of function, both alleles needed: Knudson two-hit), genes that regulate apoptosis, and DNA repair genes.
- p53 is the "guardian of the genome" (mutated in about half of all cancers); RB controls the G1/S checkpoint; RAS is the commonest mutated oncogene; BCR-ABL (Philadelphia chromosome) drives CML; BCL2 over-expression (t(14;18)) blocks apoptosis in follicular lymphoma.
- Carcinogens: chemical (initiators that mutate DNA, then promoters), radiation (UV, ionising) and microbes (HPV: cervix; EBV: Burkitt, nasopharyngeal; HBV/HCV: liver; HTLV-1: T-cell leukaemia; H. pylori: gastric cancer and MALT lymphoma).
On this page
Overview
Carcinogenesis is the process that turns a normal cell into a cancer cell. Its basis is non-lethal genetic damage (mutation), which can be inherited (germ line) or acquired from the environment (chemicals, radiation, viruses). The tumour grows from one cell that acquired the damage (clonal).
Four classes of normal genes are the targets:
| Gene class | Normal role | In cancer |
|---|---|---|
| Proto-oncogenes | Promote growth | Mutated to oncogenes: gain of function, act dominantly (one allele is enough) |
| Tumour suppressor genes | Brake growth | Loss of function; usually both alleles must be lost |
| Apoptosis-regulating genes | Control cell death | Cell death is blocked (for example, BCL2 over-expression) |
| DNA repair genes | Fix DNA damage | Mutations build up quickly (a "mutator" state) |
Hallmarks of cancer
- Self-sufficiency in growth signals (oncogenes).
- Insensitivity to growth-inhibitory signals (tumour suppressor loss).
- Evasion of apoptosis.
- Limitless replicative potential (telomerase reactivated, so telomeres do not shorten).
- Sustained angiogenesis (VEGF).
- Invasion and metastasis.
- Altered cell metabolism (aerobic glycolysis: the Warburg effect).
- Evasion of the immune system.
Enabling factors: genomic instability and tumour-promoting inflammation.
Oncogenes
| Oncogene | Activation | Associated tumours |
|---|---|---|
| RAS (KRAS) | Point mutation | The commonest mutated oncogene: pancreas, colon, lung adenocarcinoma |
| HER2 (ERBB2) | Amplification | Breast cancer (target of trastuzumab) |
| MYC | Translocation t(8;14) | Burkitt lymphoma |
| N-MYC | Amplification | Neuroblastoma |
| BCR-ABL | Translocation t(9;22) (Philadelphia chromosome) | CML, some ALL (target of imatinib) |
| RET | Point mutation | MEN 2, medullary thyroid carcinoma |
| BRAF | Point mutation | Melanoma, papillary thyroid carcinoma, hairy cell leukaemia |
| Cyclin D1 | Translocation t(11;14) | Mantle cell lymphoma |
Tumour suppressor genes
| Gene | Function | Inherited syndrome / tumours |
|---|---|---|
| RB | Holds cells at the G1/S checkpoint | Retinoblastoma, osteosarcoma |
| TP53 (p53) | "Guardian of the genome": senses DNA damage, stops the cycle at G1/S for repair, or triggers apoptosis | Li-Fraumeni syndrome (many cancers); mutated in about half of all human cancers |
| APC | Breaks down β-catenin (WNT pathway) | Familial adenomatous polyposis, colon cancer |
| BRCA1, BRCA2 | DNA repair (homologous recombination) | Breast and ovarian cancer (BRCA2 also male breast, pancreas, prostate) |
| NF1 | Inhibits RAS | Neurofibromatosis type 1 |
| WT1 | Kidney development | Wilms tumour |
| VHL | Breaks down HIF | Von Hippel-Lindau disease, renal cell carcinoma |
| CDKN2A (p16) | Inhibits cyclin-dependent kinases | Melanoma, pancreas |
Knudson two-hit hypothesis
Both copies of a tumour suppressor gene must be lost for a tumour to develop.
- Familial retinoblastoma: the child inherits one mutated RB allele in every cell; only one more hit is needed, so tumours are often bilateral and appear early; later risk of osteosarcoma.
- Sporadic retinoblastoma: both hits must occur in the same retinal cell, so it is unilateral and appears later.
Oncogene = accelerator stuck on (one hit). Tumour suppressor = brake lost (two hits).
Evasion of apoptosis
BCL2 blocks apoptosis. In follicular lymphoma, the t(14;18) translocation places BCL2 next to the immunoglobulin heavy-chain gene, so B cells over-express it and live too long.
DNA repair defects
- Hereditary non-polyposis colorectal cancer (Lynch syndrome): mismatch repair genes; colon, endometrium, ovary; microsatellite instability.
- Xeroderma pigmentosum: nucleotide excision repair; cannot repair UV damage (thymine dimers) → skin cancers.
- BRCA1/2: homologous recombination repair.
- Ataxia-telangiectasia, Bloom syndrome, Fanconi anaemia.
Multistep carcinogenesis
Cancer needs several mutations over time. The classic model is the colon adenoma-carcinoma sequence: normal mucosa → APC loss (adenoma) → KRAS mutation (larger adenoma) → p53 loss → carcinoma.
Chemical carcinogenesis
Steps:
- Initiation: a carcinogen causes a permanent DNA mutation. On its own it does not cause a tumour. It is irreversible.
- Promotion: a promoter makes the initiated cells proliferate. Promoters are not mutagenic, and their effect is reversible. The promoter must act after the initiator.
- Progression: further mutations lead to cancer.
Direct-acting carcinogens need no metabolic change (alkylating agents such as cyclophosphamide); indirect-acting (procarcinogens) are activated in the body, often by cytochrome P450.
| Carcinogen | Cancer |
|---|---|
| Tobacco smoke (polycyclic hydrocarbons, benzo[a]pyrene, nitrosamines) | Lung, oral cavity, larynx, oesophagus, bladder, pancreas |
| Betel nut, gutka, naswar, smokeless tobacco | Oral squamous cell carcinoma (a major cancer in Pakistan) |
| Aflatoxin B1 (Aspergillus flavus on stored grains and nuts) | Hepatocellular carcinoma (characteristic p53 mutation) |
| Asbestos | Bronchogenic carcinoma (most common asbestos cancer), mesothelioma |
| Aromatic amines (β-naphthylamine, aniline dyes) | Bladder cancer (rubber and dye workers) |
| Vinyl chloride | Angiosarcoma of liver |
| Arsenic | Skin, lung, liver (angiosarcoma) |
| Benzene | Acute myeloid leukaemia |
| Nitrosamines (smoked and preserved foods) | Stomach, oesophagus |
| Alkylating drugs | Leukaemia, lymphoma |
| Diethylstilboestrol (in utero) | Clear cell adenocarcinoma of the vagina |
Radiation carcinogenesis
- Ultraviolet (UVB) light: pyrimidine (thymine) dimers in DNA → basal cell carcinoma (commonest), squamous cell carcinoma, melanoma; most in fair-skinned people with heavy sun exposure.
- Ionising radiation (X-rays, gamma rays, atomic bombs, radiotherapy): double-strand breaks → leukaemia (most common, with a short latency), papillary thyroid carcinoma (especially after childhood exposure), breast, lung.
Microbial carcinogenesis
| Agent | Cancer | Mechanism |
|---|---|---|
| HPV 16, 18 (high risk) | Cervical cancer, anal, oropharyngeal | E6 inactivates p53; E7 inactivates RB |
| HPV 6, 11 (low risk) | Genital warts (condyloma) | Benign |
| EBV | Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin lymphoma, lymphomas in immunosuppressed patients | Drives B-cell proliferation |
| Hepatitis B and C | Hepatocellular carcinoma | Chronic inflammation and regeneration (HBV also integrates; HBx protein) |
| HTLV-1 | Adult T-cell leukaemia/lymphoma | Tax protein |
| HHV-8 | Kaposi sarcoma, primary effusion lymphoma | Especially in HIV |
| Helicobacter pylori | Gastric adenocarcinoma, MALT lymphoma | Chronic inflammation |
| Schistosoma haematobium | Squamous cell carcinoma of the bladder | Chronic inflammation |
| Liver flukes (Clonorchis) | Cholangiocarcinoma | Chronic inflammation |
HPV E6 → p53, E7 → RB. Aflatoxin → liver. Vinyl chloride → angiosarcoma of liver. Asbestos → lung cancer (commonest) and mesothelioma.
Expect: oncogene vs tumour suppressor gene, examples (RAS, HER2, MYC, BCR-ABL; RB, p53, APC, BRCA), Knudson two-hit with retinoblastoma, translocations t(9;22), t(8;14), t(14;18), hallmarks of cancer, initiation vs promotion, specific chemical carcinogens and their cancers, UV vs ionising radiation, and oncogenic viruses with HPV E6/E7.
Quick revision
- Four gene classes: proto-oncogenes, tumour suppressors, apoptosis genes, DNA repair genes.
- RAS: commonest oncogene. p53: commonest tumour suppressor.
- Two-hit: familial retinoblastoma is bilateral and early.
- t(9;22) CML; t(8;14) Burkitt; t(14;18) follicular lymphoma.
- Initiation (irreversible mutation) → promotion (reversible) → progression.
- Aflatoxin: liver. Vinyl chloride: liver angiosarcoma. Aniline dyes: bladder. Asbestos: lung, mesothelioma.
- HPV 16/18 (E6-p53, E7-RB); EBV (Burkitt, nasopharynx); HBV/HCV (liver); H. pylori (stomach, MALT).
Written by The House Job from standard pathology references (Robbins and Cotran Pathologic Basis of Disease is the book named in the UHS PGET syllabus).
FAQ
What is the difference between an oncogene and a tumour suppressor gene?
An oncogene is a mutated growth-promoting gene that acts with one altered copy (gain of function); a tumour suppressor gene normally restrains growth and usually causes cancer only when both copies are lost.
What is Knudson's two-hit hypothesis?
Both alleles of a tumour suppressor gene must be inactivated for a tumour to form; in familial retinoblastoma one hit is inherited, so the tumour appears earlier and is often bilateral.
Which carcinogen is linked to hepatocellular carcinoma?
Aflatoxin B1 from Aspergillus flavus, together with chronic hepatitis B and C infection.
How does HPV cause cervical cancer?
High-risk types (16 and 18) produce the E6 protein, which inactivates p53, and the E7 protein, which inactivates RB.