title: Loss of function germline mutations in RAD51D in women with ovarian carcinoma.
abstract: OBJECTIVE
  RAD51D, a gene in the Fanconi Anemia-BRCA homologous recombination pathway, has recently been shown to harbor germline mutations responsible for ovarian carcinoma in multiply affected families. We aimed to extend these results to ovarian carcinoma in the general population.
  
  
  METHODS
  We sequenced RAD51D in germline DNA from 360 individuals with primary ovarian, peritoneal or fallopian tube carcinoma who were not selected for age of cancer onset or family history. We also sequenced RAD51D in 459 probands from 226 high risk breast cancer families who were wild type for 21 breast and ovarian cancer genes.
  
  
  RESULTS
  Of 360 cases, three (0.8%) carried loss-of-function mutations in RAD51D. All three subjects had ovarian carcinoma; one was also diagnosed with a synchronous endometrial carcinoma. Only one of the three subjects had a family history of breast or ovarian cancer. Combined with previous data for this series, 23.9% of women with unselected ovarian, fallopian tube, or peritoneal carcinoma carried a germline loss-of-function mutation in any of 13 tumor suppressor genes. Among the 449 women and 10 men with familial breast cancer, none carried a loss of function mutation in RAD51D.
  
  
  CONCLUSIONS
  These data support the previous observation that loss-of-function mutations in RAD51D predispose to ovarian carcinoma but not to breast carcinoma. We conclude that inherited ovarian cancer is highly heterogeneous genetically, and that approximately one in four ovarian carcinoma patients carry a germline mutation in a known tumor suppressor gene that confers high risk.
authors.forename: Anneka
authors.initials: A
authors.lastname: Wickramanayake
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Anneka
authors.initials: A
authors.lastname: Wickramanyake
authors.forename: Greta
authors.initials: G
authors.lastname: Bernier
authors.forename: Christopher
authors.initials: C
authors.lastname: Pennil
authors.forename: Silvia
authors.initials: S
authors.lastname: Casadei
authors.forename: Kathy J
authors.initials: KJ
authors.lastname: Agnew
authors.forename: Sunday M
authors.initials: SM
authors.lastname: Stray
authors.forename: Jessica
authors.initials: J
authors.lastname: Mandell
authors.forename: Rochelle L
authors.initials: RL
authors.lastname: Garcia
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Swisher
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C112629:RAD51D protein, human