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

Yuexin Liu, Maya Yasukawa, Kexin Chen, Limei Hu, Russell R. Broaddus, Li Ding, Elaine R. Mardis, Paul Spellman, Douglas A. Levine, Gordon B. Mills, Ilya Shmulevich, Anil K. Sood, Wei Zhang

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Abstract

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.

Original languageEnglish
Pages (from-to)486-494
Number of pages9
JournalJAMA oncology
Volume1
Issue number4
DOIs
StatePublished - Jan 1 2015

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    Liu, Y., Yasukawa, M., Chen, K., Hu, L., Broaddus, R. R., Ding, L., Mardis, E. R., Spellman, P., Levine, D. A., Mills, G. B., Shmulevich, I., Sood, A. K., & Zhang, W. (2015). Association of somatic mutations of ADAMTS genes with chemotherapy sensitivity and survival in high-grade serous ovarian carcinoma. JAMA oncology, 1(4), 486-494. https://doi.org/10.1001/jamaoncol.2015.1432