Key points
- Oncogenes are accelerators stuck on: one faulty copy is enough.
- Tumour suppressors are brakes that fail: both copies must be lost (two hits).
- Mismatch repair failure causes microsatellite instability (MSI) and Lynch syndrome.
- Molecular results now decide treatment: HER2, RAS, BRAF, MSI and BRCA.
Two kinds of cancer gene
| Oncogenes | Tumour suppressor genes | |
|---|---|---|
| Normal job | Promote growth (proto-oncogenes) | Stop growth, repair DNA, trigger apoptosis |
| In cancer | Gain of function: the accelerator is stuck on | Loss of function: the brakes fail |
| Copies affected | One is enough (dominant) | Both must be lost (recessive at cell level) |
| Examples | KRAS, HER2 (ERBB2), MYC, BRAF, EGFR, RET | TP53, RB1, APC, BRCA1/2, VHL, PTEN, CDH1 |
Knudson’s two-hit hypothesis
For a tumour suppressor gene, both alleles must be inactivated. In inherited cancer, the first hit is present in every cell from birth, so only one more hit is needed: cancers appear younger, in both organs (bilateral) and in more than one site. In sporadic cancer, both hits must happen by chance in the same cell.
DNA repair genes
- Mismatch repair (MLH1, MSH2, MSH6, PMS2): failure causes errors in repetitive DNA, called microsatellite instability (MSI). Germline faults cause Lynch syndrome.
- Homologous recombination (BRCA1, BRCA2): faulty cells depend on another repair enzyme, PARP. Blocking it with a PARP inhibitor kills them: an example of synthetic lethality.
The adenoma–carcinoma sequence
Vogelstein’s model of colorectal cancer: APC loss (normal mucosa to early adenoma) → KRAS activation (larger adenoma) → loss of chromosome 18q/SMAD4 → TP53 loss (carcinoma). Two other routes exist: the MSI pathway and the serrated (BRAF) pathway.
Why surgeons need this now
| Test | What it changes |
|---|---|
| HER2 (breast, stomach) | Trastuzumab and other anti-HER2 treatment |
| RAS and BRAF (colorectal) | Anti-EGFR antibodies work only in RAS wild-type tumours; BRAF V600E has its own targeted treatment |
| MSI / mismatch repair (colorectal, endometrial, stomach) | Screens for Lynch syndrome; MSI-high tumours respond very well to immunotherapy |
| BRCA (breast, ovary, pancreas, prostate) | PARP inhibitors; risk-reducing surgery; testing the family |
| RET (medullary thyroid) | Prophylactic thyroidectomy in carriers; selective RET inhibitors |
| KIT (GIST) | Imatinib |
Germline or somatic?
A germline mutation is inherited and present in every cell: it matters for the family. A somatic mutation exists only in the tumour: it matters for treatment.
Frequently asked questions
What is the difference between an oncogene and a tumour suppressor gene?
An oncogene drives growth when it is switched on, and one faulty copy is enough. A tumour suppressor gene stops growth, and both copies must be lost before control fails.
What is the two-hit hypothesis?
Knudson's idea that both copies of a tumour suppressor gene must be inactivated. In inherited cancer the first hit is present from birth, so cancers appear younger and in more than one site.
What is microsatellite instability?
Errors in repetitive DNA caused by failed mismatch repair. It is the hallmark of Lynch syndrome, and MSI-high tumours respond well to immunotherapy.
Further reading
- Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971;68:820–3.
- Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759–67.