In the context of hereditary ovarian cancer risk reduction, the BRCA1 mutation confers a lifetime risk of ovarian cancer of approximately 44% versus 17% for BRCA2. PARP (poly-ADP ribose polymerase) inhibitor maintenance therapy exploits which cellular mechanism in BRCA-mutated tumours?
- A Epigenetic silencing of oncogenes via histone deacetylation
- B Synthetic lethality — PARP inhibition in cells already deficient in homologous recombination repair leads to irreparable double-strand DNA breaks ✓
- C Downregulation of VEGF expression, reducing tumour neovascularisation
- D Inhibition of mTOR signalling, preventing cell cycle progression
Explanation
BRCA1/2 proteins are essential for homologous recombination (HR) repair of double-strand DNA breaks. PARP1 normally repairs single-strand DNA breaks via base excision repair. When PARP is inhibited in BRCA-mutated cells, single-strand breaks become double-strand breaks that cannot be repaired by HR (because BRCA1/2 are non-functional) — this 'synthetic lethality' leads to tumour cell death selectively, sparing normal cells with intact BRCA. Olaparib (SOLO-1 trial, 2018), niraparib (PRIMA trial, 2019), and rucaparib are approved PARP inhibitors for maintenance therapy in BRCA-mutated ovarian cancer.
Reference: Shaw's Textbook of Gynaecology, 17th ed.
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Written and medically reviewed by the StethoPrep medical team.