title: Genetic characterization of early onset ovarian carcinoma.
abstract: OBJECTIVE
  Ovarian carcinoma (OC) is rare in young women and the fraction of early onset OC attributable to inherited mutations in known OC genes is uncertain. We sought to characterize the fraction of OC that is heritable in women diagnosed with ovarian, fallopian tube, or peritoneal carcinoma at forty years of age or younger.
  
  
  METHODS
  We sequenced germline DNA from forty-seven women diagnosed with OC at age 40 or younger ascertained through a gynecologic oncology tissue bank or referred from outside providers using BROCA, a targeted capture and massively parallel sequencing platform that can detect all mutation classes. We evaluated 11 genes associated with ovarian carcinoma (BARD1, BRCA1, BRCA2, BRIP1, MLH1, MSH2, MSH6, PALB2, PMS2, RAD51D, and RAD51C) and additional candidate genes in DNA repair (ATM, BAP1, CHEK2, MRE11A, NBN, PTEN, TP53). We counted only clearly damaging mutations.
  
  
  RESULTS
  Damaging mutations in OC genes were identified in 13 of 47 (28%) subjects, of which 10 (77%) occurred in BRCA1 and one each occurred in BRCA2, MSH2, and RAD51D. Women with a strong family history were no more likely to have an OC gene mutation (8/17, 47%) than those without a strong family history (9/30, 30%, P=0.35). Additionally, damaging mutations in non-OC genes were identified, one in NBN and one in CHEK2.
  
  
  CONCLUSIONS
  A high proportion of young women with invasive OC have mutations in BRCA1, and a smaller fraction have mutations in other known OC genes. Family history was not associated with mutation status in these early onset cases.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 Northeast Pacific Street, Seattle, WA 98195, USA. Electronic address: sarahb18@uw.edu.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Bernards
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 Northeast Pacific Street, Seattle, WA 98195, USA. Electronic address: bnorquis@uw.edu.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Norquist
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 Northeast Pacific Street, Seattle, WA 98195, USA. Electronic address: maribel@uw.edu.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Harrell
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 Northeast Pacific Street, Seattle, WA 98195, USA. Electronic address: kagnew@uw.edu.
authors.forename: Kathy J
authors.initials: KJ
authors.lastname: Agnew
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, 1959 Northeast Pacific Street, Seattle, WA 98195, USA. Electronic address: mlee@uw.edu.
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, 1959 Northeast Pacific Street, Seattle, WA 98195, USA. Electronic address: twalsh@uw.edu.
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 Northeast Pacific Street, Seattle, WA 98195, USA; Division of Medical Genetics, Department of Medicine, University of Washington, 1959 Northeast Pacific Street, Seattle, WA 98195, USA. Electronic address: swishere@uw.edu.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Swisher
mesh_terms: D000328:Adult; D017668:Age of Onset; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006801:Humans; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010375:Pedigree
chemical_list: D004268:DNA-Binding Proteins; C112629:RAD51D protein, human; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein
keywords: BRCA1; BRCA2; Carcinoma; Inherited; Ovarian; Young