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Cancer molecular biology — oncogenes, tumour suppressor genes and DNA repair
Cancer arises when oncogenes are activated (a hit in one allele is enough) and tumour suppressor genes lose function (two hits are needed); defects in DNA repair systems — MMR and homologous recombination — create tumours with features that can be exploited in treatment.
Why it matters in the exam
The bank includes recurring basic questions: which gene is a tumour suppressor, how reduced APC expression causes colon cancer, what is true about MSI and MMR, what an HRD test includes, which syndromes are linked to sebaceous gland tumours, and in which cancers genetic referral is made regardless of family history.
In Israel this has special meaning: the three founder mutations in BRCA1 and BRCA2 occur in about 1 in 40 Ashkenazi Jews, so every woman of Ashkenazi origin with breast or ovarian cancer is referred for testing even without a family history. The molecular groups of endometrial cancer, which set prognosis and treatment, are also asked.
Key points
- Oncogenes are activated in one allele, and tumour suppressor genes need a hit in both alleles.
- Loss of APC prevents degradation of β-catenin, which accumulates in the nucleus and activates division and growth genes.
- An MMR defect causes MSI; germline — Lynch, and sporadic — mainly MLH1 methylation, sometimes with BRAF V600E.
- HRD includes defects in BRCA and other genes, is also measured as a genomic scar, and predicts response to platinum and PARP inhibitors.
- In ovarian, pancreatic and metastatic prostate cancer genetic referral is always made, and in Israel also every Ashkenazi woman with breast cancer.
Summary table
| Issue | Key points | Examples and meaning |
|---|---|---|
| Oncogenes | An activating hit in one allele; amplification, mutation or fusion | RAS, MYC, HER2, EGFR, BRAF, ALK fusion |
| Tumour suppressor genes | Both alleles must be hit (two hits) | TP53, RB1, APC, BRCA1 and BRCA2, VHL, PTEN, NF1 |
| APC and the WNT pathway | APC is part of the complex that degrades β-catenin | Loss of APC — β-catenin accumulates in the nucleus and activates division genes |
| MMR and MSI | MLH1, MSH2, MSH6, PMS2; a defect — unstable microsatellites | Germline — Lynch syndrome (including sebaceous gland tumours — Muir-Torre); sporadic — MLH1 methylation, sometimes with BRAF V600E |
| Homologous recombination and HRD | BRCA1, BRCA2, PALB2, RAD51 and others; HRD is also measured as a "genomic scar" — loss of heterozygosity and telomeric imbalance | Sensitivity to platinum and PARP inhibitors (synthetic lethality) |
| Genetic referral regardless of family | Ovarian, pancreatic, metastatic prostate cancer, male breast cancer, triple-negative breast cancer at young age | In Israel: every Ashkenazi patient with breast or ovarian cancer — founder mutation testing |
| Molecular groups in the endometrium | POLE (excellent prognosis), MSI, no specific profile, and copy-number high with TP53 (the worst) | The classification changes adjuvant treatment and immunotherapy |
A free exam question
איזה מהמוטציות הסומאטיות הבאות היא בעלת השכיחות הגבוהה ביותר בסרטן שד IDC ER positive PR positive HER2 negative ? (the question as examined, in Hebrew)
- א. BRCA1
- ב. BRCA2
- ג. CHEK2
- ד. PIK3CA
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Sources
- Weinberg, The Biology of Cancer, 2nd ed. (2014) — Tumor suppressor genes; Maintenance of genomic integrity
- NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic and Prostate, 2026 — Testing criteria
- Cancer Genome Atlas Research Network, Integrated genomic characterization of endometrial carcinoma, 2013 — Molecular subgroups
Sources are given for further reading; the text is written afresh and not copied from them.
Reviewed by the Examqo AI Professor · 2026-11-06. The text may contain errors; when in doubt, check the source.