Association of somatic mutations of ADAMTS genes with chemotherapy sensitivity and survival in high-grade serous ovarian carcinoma

IMPORTANCE: Chemotherapy response in the majority of patients with ovarian cancer remains unpredictable. OBJECTIVE:To identify novel molecular markers for predicting chemotherapy response in patients with ovarian cancer. DESIGN, SETTING, AND PARTICIPANTS: Observational study of genomics and clinical data of high-grade serous ovarian cancer cases with genomic and clinical data made public between 2009 and 2014 via the Cancer Genome Atlas project. MAINOUTCOMES ANDMEASURES: Chemotherapy response (primary outcome) and overall survival (OS), progression-free survival (PFS), and platinum-free duration (secondary outcome). RESULTS: In 512 patients with ovarian cancer with available whole-exome sequencing data, mutations from 8 members ofthe ADAMTS family (ADAMTS mutations) with an overall mutation rate of approximately 10.4% were associated with a significantly higher chemotherapy sensitivity (100% for ADAMTS-mutatedvs 64% for ADAMTS wild-type cases; P <.001) and longer platinum-free duration (median platinum-free duration, 21.7 months for ADAMTS-mutated vs 10.1 months for ADAMTS wild-type cases; P =.001). Moreover, ADAMTS mutations were associated with significantly better OS (hazard ratio [HR], 0.54 [95% CI, 0.42-0.89]; P =.01 and median OS, 58.0 months for ADAMTS-mutated vs 41.3 months for ADAMTS wild-type cases) and PFS (HR, 0.42 [95% CI, 0.38-0.70];P <.001 and median PFS, 31.8 for ADAMTS-mutated vs15.3 months for ADAMTS wild-type cases). After adjustment by BRCA1 or BRCA2 mutation, surgical stage, residual tumor, and patient age, ADAMTS mutations were significantly associated with better OS (HR, 0.53 [95% CI, 0.32-0.87]; P =.01), PFS (HR, 0.40 [95% CI, 0.25-0.62]; P <.001), and platinum-free survival (HR, 0.45 [95% CI, 0.28-0.73]; P =.001). ADAMTS-mutated cases exhibited a distinct mutation spectrum and were significantly associated with tumors with a higher genome-wide mutation rate than ADAMTS wild-type cases across the whole exome (median mutation number per sample, 121 for ADAMTS-mutated vs 69 for ADAMTS wild-type cases; P <.001). CONCLUSIONS AND RELEVANCE:ADAMTS mutations may contribute to out comes in ovarian cancer cases without BRCA1 or BRCA2 mutations and may have important clinical implications.