title: Association of Somatic Mutations of ADAMTS Genes With Chemotherapy Sensitivity and Survival in High-Grade Serous Ovarian Carcinoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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 of the ADAMTS family (ADAMTS mutations) with an overall mutation rate of approximately 10.4% were associated with a significantly higher chemotherapy sensitivity (100% for ADAMTS-mutated vs 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 vs 15.3 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
  ADAMTS mutations may contribute to outcomes in ovarian cancer cases without BRCA1 or BRCA2 mutations and may have important clinical implications.
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston2Institute for Systems Biology/MD Anderson Cancer Center Genome Data Analysis Center, The Cancer Genome Atlas, Bethesda, Maryland.
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston3Department of Obstetrics and Gynecology, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan.
authors.forename: Maya
authors.initials: M
authors.lastname: Yasukawa
authors.affiliation: Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Hospital and Institute, Tianjin, PR China.
authors.forename: Kexin
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Limei
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.affiliation: Genome Institute, Washington University, St Louis, Missouri.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.affiliation: Genome Institute, Washington University, St Louis, Missouri.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland.
authors.forename: Paul
authors.initials: P
authors.lastname: Spellman
authors.affiliation: Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Levine
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Institute for Systems Biology/MD Anderson Cancer Center Genome Data Analysis Center, The Cancer Genome Atlas, Bethesda, Maryland9Institute for Systems Biology, Seattle, Washington.
authors.forename: Ilya
authors.initials: I
authors.lastname: Shmulevich
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston11Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston2Institute for Systems Biology/MD Anderson Cancer Center Genome Data Analysis Center, The Cancer Genome Atlas, Bethesda, Maryland.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D009154:Mutation; D060787:Neoplasm Grading; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D010641:Phenotype; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor; D051722:ADAM Proteins