DNA repair defects, microsatellite instability and synthetic lethality
The main DNA repair pathways and the syndromes caused by losing them, how mismatch repair loss produces microsatellite instability and checkpoint inhibitor sensitivity, and why PARP inhibitors kill homologous recombination-deficient tumours.
Tier 2Medical sciences concept
Written with AI assistance and fact-checked against the sources below. For exam study, not clinical decisions. How notes are made
At a glance
- Cells repair thousands of DNA lesions a day. Each pathway handles a type of damage, and each has an inherited syndrome when it fails.
- Repair genes are caretaker tumour suppressors. Losing both alleles raises the mutation rate, so other drivers accumulate fast (see oncogenes and tumour suppressors).
- Mismatch repair (MMR) loss produces microsatellite instability (MSI): in Lynch syndrome, in sporadic tumours through MLH1 promoter methylation, and as the reason dMMR tumours respond to PD-1 blockade.
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Sources
- Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategyNature (Farmer et al., 2005;434:917-21), 2005
- PARP inhibitors: synthetic lethality in the clinicScience (Lord and Ashworth, 2017;355:1152-8), 2017
- PD-1 blockade in tumors with mismatch-repair deficiencyNEJM (Le et al., 2015;372:2509-20), 2015
- Pembrolizumab in microsatellite-instability-high advanced colorectal cancer (KEYNOTE-177)NEJM (André et al., 2020;383:2207-18), 2020
- Pembrolizumab versus chemotherapy for MSI-high or dMMR metastatic colorectal cancer (KEYNOTE-177): final analysisLancet Oncology (Diaz et al., 2022;23:659-70), 2022
- Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer (SOLO-1)NEJM (Moore et al., 2018;379:2495-505), 2018
- Olaparib plus bevacizumab as first-line maintenance in ovarian cancer (PAOLA-1)NEJM (Ray-Coquard et al., 2019;381:2416-28), 2019
- Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer (POLO)NEJM (Golan et al., 2019;381:317-27), 2019
- Clinical practice guidelines for the prevention, early detection and management of colorectal cancer (Lynch syndrome testing)AU/NZCancer Council Australia
- Hereditary cancer risk management guidelinesAU/NZeviQ, Cancer Institute NSW
- Robbins and Cotran Pathologic Basis of DiseaseElsevier (Kumar, Abbas and Aster)
- Last updated
- 14 November 2026
What changed
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