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Original Investigation
April 2016

Inherited Mutations in Women With Ovarian Carcinoma

Author Affiliations
  • 1Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle
  • 2The NRG Oncology Statistical and Data Center, Roswell Park Cancer Center Institute, Buffalo, New York
  • 3Division of Medical Genetics, Department of Medicine, University of Washington, Seattle
  • 4Department of Genome Sciences, University of Washington, Seattle
  • 5Division of Gynecologic Oncology, University of Pennsylvania, Philadelphia
  • 6Division of Gynecologic Oncology, Sutter Health California Pacific Medical Center, San Francisco, California
  • 7Division of Gynecologic Oncology, University of Colorado, Denver
  • 8Division of Gynecologic Oncology, University of Oklahoma, Oklahoma City
  • 9Division of Gynecologic Oncology, Women and Infants Hospital, Providence, Rhode Island
  • 10Department of Pathology and Laboratory Medicine, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio
  • 11Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston
JAMA Oncol. 2016;2(4):482-490. doi:10.1001/jamaoncol.2015.5495

Importance  Germline mutations in BRCA1 and BRCA2 are relatively common in women with ovarian, fallopian tube, and peritoneal carcinoma (OC) causing a greatly increased lifetime risk of these cancers, but the frequency and relevance of inherited mutations in other genes is less well characterized.

Objective  To determine the frequency and importance of germline mutations in cancer-associated genes in OC.

Design, Setting, and Participants  A study population of 1915 woman with OC and available germline DNA were identified from the University of Washington (UW) gynecologic tissue bank (n = 570) and from Gynecologic Oncology Group (GOG) phase III clinical trials 218 (n = 788) and 262 (n = 557). Patients were enrolled at diagnosis and were not selected for age or family history. Germline DNA was sequenced from women with OC using a targeted capture and multiplex sequencing assay.

Main Outcomes and Measures  Mutation frequencies in OC were compared with the National Heart, Lung, and Blood Institute GO Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC). Clinical characteristics and survival were assessed by mutation status.

Results  Overall, the median (range) age at diagnosis was 60 (28-91) years in patients recruited from UW and 61 (23-87) years in patients recruited from the GOG trials. A higher number of black women were recruited from the GOG trials (4.3% vs 1.4%; P = .009); but in patients recruited from UW, there was a higher proportion of fallopian tube carcinomas (13.3% vs 5.7%; P < .001); stage I and II disease (14.6% vs 0% [GOG trials were restricted to advanced-stage cancer]); and nonserous carcinomas (29.9% vs 13.1%, P < .001). Of 1915 patients, 280 (15%) had mutations in BRCA1 (n = 182), or BRCA2 (n = 98), and 8 (0.4%) had mutations in DNA mismatch repair genes. Mutations in BRIP1 (n = 26), RAD51C (n = 11), RAD51D (n = 11), PALB2 (n = 12), and BARD1 (n = 4) were significantly more common in patients with OC than in the ESP or ExAC, present in 3.3%. Race, histologic subtype, and disease site were not predictive of mutation frequency. Patients with a BRCA2 mutation from the GOG trials had longer progression-free survival (hazard ratio [HR], 0.60; 95% CI, 0.45-0.79; P < .001) and overall survival (HR, 0.39; 95% CI, 0.25-0.60; P < .001) compared with those without mutations.

Conclusions and Relevance  Of 1915 patients with OC, 347 (18%) carried pathogenic germline mutations in genes associated with OC risk. PALB2 and BARD1 are suspected OC genes and together with established OC genes (BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH2, MLH1, PMS2, and MSH6) bring the total number of genes suspected to cause hereditary OC to 11.