Tumour suppressor genes: RB, TP53, APC, BRCA and the two-hit hypothesis !
- Topic
Tumour suppressors are the cell's brakes. Cancer needs both copies broken, and people born with one broken copy get cancer earlier.
Updated 2026-11-01
What it is
Tumour suppressor genes encode proteins that restrain proliferation, repair DNA or trigger death of damaged cells. Their loss of function needs both alleles to be inactivated, as Knudson's two-hit hypothesis explained from retinoblastoma. A person who inherits one defective allele needs only one more somatic hit, which is why hereditary cancers appear earlier, are often bilateral or multiple, and run in families.
Step by step
- Hereditary case: every cell of the body already carries one defective allele (first hit, germline).
- A single somatic event in one cell (mutation, deletion or loss of heterozygosity) removes the remaining normal allele.
- With no working brake, that cell proliferates and accumulates more mutations.
- Sporadic case: both hits must happen by chance in the same cell, which is rare and takes longer.
- Result: hereditary tumours appear younger, more often bilateral or multifocal; sporadic ones are later and single.
Tumour suppressors to know
| Gene | Normal function | Hereditary syndrome | Typical tumours |
|---|---|---|---|
| RB1 | Holds E2F; blocks G1 to S | Familial retinoblastoma | Retinoblastoma, osteosarcoma |
| TP53 | Cell-cycle arrest, repair, apoptosis | Li-Fraumeni syndrome | Sarcomas, breast, brain, adrenal cortex, leukaemia |
| APC | Degrades beta-catenin | Familial adenomatous polyposis | Colorectal adenomas and carcinoma |
| BRCA1, BRCA2 | Homologous recombination repair | Hereditary breast and ovarian cancer | Breast, ovary, prostate, pancreas |
| NF1 | RAS GTPase-activating protein (neurofibromin) | Neurofibromatosis type 1 | Neurofibromas, malignant nerve sheath tumours |
| VHL | Degrades HIF | Von Hippel-Lindau syndrome | Clear cell renal carcinoma, haemangioblastoma, pheochromocytoma |
| WT1 | Kidney and gonad development | WAGR and related syndromes | Wilms tumour |
| CDKN2A (p16) | Inhibits CDK4/6 | Familial melanoma | Melanoma, pancreatic cancer |
| PTEN | Brakes the PI3K-AKT pathway | Cowden syndrome | Breast, endometrial, thyroid cancers |
Clinical notes
- Familial retinoblastoma is often bilateral and appears in infancy; survivors have a high risk of osteosarcoma.
- Carriers of BRCA mutations are offered intensified screening and risk-reducing options; their tumours respond to PARP inhibitors.
- Li-Fraumeni families show many different cancers at young ages.
Test yourself
Think of the answer, then tap the question to see it.
What does Knudson's two-hit hypothesis state?
Both alleles of a tumour suppressor gene must be inactivated for a tumour to arise; in hereditary cases the first hit is inherited, so only one somatic hit is needed.
How does RB control the cell cycle?
Hypophosphorylated RB binds E2F and prevents entry into S phase; cyclin D-CDK4/6 phosphorylate RB to release E2F.
Which syndrome results from a germline TP53 mutation?
Li-Fraumeni syndrome: early sarcomas, breast cancer, brain tumours, adrenocortical carcinoma and leukaemias.
How does high-risk HPV inactivate tumour suppressors?
Its E6 protein promotes degradation of p53 and its E7 protein binds and inactivates RB.
Related
- Oncogenes: RAS, MYC, HER2, BCR-ABL and the table to know
- The cell cycle in cancer: cyclins, CDKs and checkpoints
- Genomic instability: mismatch repair, BRCA and xeroderma pigmentosum
- Hereditary cancer syndromes: the table to know
- Multistep carcinogenesis: the adenoma–carcinoma sequence
- Evading cell death and replicating without limit: BCL2 and telomerase
Related conditions
- Retinoblastoma
- Colorectal polyps and hereditary polyposis syndromes (FAP, Lynch)
- Hereditary breast and ovarian cancer syndrome (BRCA1/BRCA2)
- Neurofibromatosis (types 1 and 2)
- Osteosarcoma
- Colorectal cancer
- Renal cell carcinoma
- Wilms tumour (nephroblastoma)
- Melanoma
- Pancreatic cancer
- Cervical cancer
- Breast cancer
- Ovarian cancer
Elsewhere in DurgiPedia
Microorganisms
Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.
Sources: TP53 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); RB1 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); APC gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Li-Fraumeni syndrome: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026).
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