Bit · Pathology
Oncogenes vs Tumor Suppressor Genes
Two ways genes drive cancer. Oncogenes push the accelerator; tumor suppressors release the brake. The genetics of how they break is opposite.
Mechanism
Cancer arises when a cell escapes normal proliferation control. There are two ways to break the control:
- Proto-oncogenes — normal genes that promote growth (receptor tyrosine kinases, transcription factors, cell-cycle drivers). When activated by mutation, amplification, or translocation, they become oncogenes. One mutated allele is enough ('gain of function' — dominant at the cellular level).
- Tumor suppressor genes — normal genes that restrain growth (cell cycle checkpoints, DNA repair, apoptosis). To eliminate the brake, both alleles must be lost ('loss of function' — recessive at the cellular level). Knudson 'two-hit' hypothesis: in hereditary cancer syndromes, one defective allele is inherited; a second somatic hit eliminates the other.
Differentiator Table
| Oncogenes | Tumor suppressors | |
| Normal function | Promote proliferation | Restrain proliferation; repair DNA; trigger apoptosis |
| Mutation type | GAIN of function | LOSS of function |
| Alleles needed to lose | 1 (dominant at cellular level) | BOTH (recessive at cellular level — 'two hits') |
| Hereditary cancer pattern | Less common | Common (one defective allele inherited) |
| Classic examples (oncogenes) | RAS (many cancers), MYC (Burkitt — t(8;14)), HER2/neu (breast), BCR-ABL (CML — t(9;22)), BCL-2 (follicular — t(14;18)), CCND1/cyclin D1 (mantle — t(11;14)), ALK (lung), RET (MEN 2) | |
| Classic examples (tumor suppressors) | TP53 (Li-Fraumeni, most cancers), RB1 (retinoblastoma, osteosarcoma), BRCA1/BRCA2 (breast, ovarian), APC (familial adenomatous polyposis), VHL (RCC, hemangioblastoma), NF1 / NF2 / TSC1/2, WT1 (Wilms), MEN1, MLH1 / MSH2 (Lynch / HNPCC) | |
| Example translocation | t(9;22) Philadelphia → BCR-ABL → CML, ALL | Not characteristic |
The Pivot
Two questions tell you which category:
- Is the mutation gain-of-function (overactive enzyme, fusion protein, amplification)? → Oncogene.
- Is the mutation loss-of-function (deletion, frameshift, nonsense mutation) AND does the disease run in families with one inherited allele plus a second somatic hit? → Tumor suppressor.
NBME often gives a translocation (e.g. t(8;14)) and asks which gene. Memorize the famous translocations: t(9;22) BCR-ABL CML; t(8;14) c-MYC Burkitt; t(14;18) BCL-2 follicular; t(15;17) PML-RARA APL; t(11;14) cyclin D1 mantle.
NBME-Style Stem
A 6-year-old girl is found to have a unilateral retinoblastoma. Her father was diagnosed with retinoblastoma in childhood and has a history of osteosarcoma. Genetic testing of the tumor reveals loss of both copies of the RB1 gene; one defective allele is found in her germline. Which of the following best describes the molecular mechanism underlying her tumor?
Concept Anchor
Oncogenes are accelerators stuck on — one activating mutation is enough to floor it. Tumor suppressors are brakes — you need to cut both before the cell rolls free. Hereditary cancer syndromes are families that already inherited one cut brake.