Clonal tumor mutations in homologous recombination genes predict favorable clinical outcome in ovarian cancer treated with platinum-based chemotherapy

Abstract

ObjectivePlatinum-based chemotherapy remains the first-line treatment for ovarian carcinoma by inducing DNA damage. The therapeutic impact of clonal and subclonal somatic mutations in DNA damage repair (DDR) pathways remains unexplored. MethodsWe performed an integrated analysis to infer the clonality of somatic deleterious mutations in 385 ovarian carcinomas treated with platinum-based chemotherapy. The Kaplan–Meier method was performed for visualization and the differences between survival curves were calculated by log-rank test. Proportional hazards models were used to estimate relative hazards for platinum-free interval (PFI), progression-free survival (PFS) and overall survival (OS). ResultsWe found that somatic deleterious mutations in DDR pathways exhibited widespread clonal heterogeneity, and that patients with DDR clonal mutations exhibited a “hypermutator phenotype”. Clonal somatic mutations in homologous recombination repair (HRR) pathway were significantly associated with better OS (HR = 0.19 (95% CI, 0.06–0.59), P = 0.0044) and PFS (HR = 0.20 (95% CI, 0.08–0.49), P = 0.0005) than HRR wild-type, while HRR subclonal mutations were not associated with prognosis. Moreover, HRR clonal mutations were associated with significantly higher chemotherapy sensitive rate (P = 0.0027) and longer PFI (HR = 0.20 (95% CI, 0.08–0.49), P = 0.0005) than HRR wild-type, while HRR subclonal mutations were not. We validated our findings using an independent cohort of 93 ovarian cancer patients that received platinum-based chemotherapy. ConclusionsHRR clonal mutations, but not subclonal mutations, were associated with improved survival, chemotherapy response, and genome instability compared with HRR wild-type.