title: A targeted analysis identifies a high frequency of BRCA1 and BRCA2 mutation carriers in women with ovarian cancer from a founder population.
abstract: BACKGROUND
  The frequency of BRCA1 and BRCA2 mutations in ovarian cancer patients varies depending on histological subtype and population investigated. The six most commonly recurring BRCA1 and BRCA2 mutations previously identified in a founder French Canadian population were investigated in 439 histologically defined ovarian, fallopian tube and primary peritoneal cancer cases that were ascertained at one hospital servicing French Canadians. To further assess the frequency of BRCA1/BRCA2 mutations, a defined subgroup of 116 cases were investigated for all mutations previously reported in this population.
  
  
  METHODS
  A PCR-based assay was used to screen 439 ovarian, fallopian tube or extra-ovarian cancers comprised of serous, high grade endometrioid and mixed cell adenocarcinomas with serous components for specific BRCA1: C4446T and 2953delGTAinsC and BRCA2: 8765delAG, G6085T, 3398del5 and E3002K mutations. A multiplex bead-array-based Luminex assay was used to evaluate 19 specific mutations that have ever been reported in French Canadians, which included the six mutations assayed by PCR, in 116 cases representing all women ascertained within a defined 3-year window.
  
  
  RESULTS
  A targeted analysis of six mutations identified 34/439 (7.7%) mutation carriers and at least two mutation carriers for each mutation screened were found. The BRCA1:C4446T mutation was the most frequently identified variant (15/34, 44.1%) among mutation-positive cases. The expanded mutation screen that also included 13 additional variants identified 19/116 (16.4%) mutation carriers, where C4446T was the most common variant (8/19, 42.1%) identified among mutation-positive carriers in this subgroup. Mutations were identified in women with serous, endometrioid, mixed cell, and undifferentiated adenocarcinomas. Within this subgroup there were 73 high-grade (G3) serous ovarian carcinomas, the most common subtype, with mutations identified in 19.2% (n = 14) serous cases.
  
  
  CONCLUSIONS
  Our results reaffirm that specific BRCA1 and BRCA2 mutations found previously to recur in French Canadian breast cancer and breast-ovarian cancer families, also recur in women with ovarian cancer not selected for family history of cancer. The high frequency of mutation carriers rationalizes genetic testing of ovarian cancer patients in this demographically defined population.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada. moria.belanger@mail.mcgill.ca.
authors.forename: Moria H
authors.initials: MH
authors.lastname: Belanger
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada. lena.dolman@mail.mcgill.ca.
authors.forename: Lena
authors.initials: L
authors.lastname: Dolman
authors.affiliation: The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. suzanna.arcand@mail.mcgill.ca.
authors.forename: Suzanna L
authors.initials: SL
authors.lastname: Arcand
authors.affiliation: Molecular Pathology Centre, Department of Pathology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada. zhen.shen@mail.mcgill.ca.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Molecular Pathology Centre, Department of Pathology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada. George.chong@mcgill.ca.
authors.forename: George
authors.initials: G
authors.lastname: Chong
authors.affiliation: Département de médecine, Université de Montréal, Montreal, Canada. anne-marie.mes-masson@umontreal.ca.|Centre de recherche du Centre Hospitalier de l'Université de Montréal and Institut du cancer de Montréal, Montreal, Quebec, Canada. anne-marie.mes-masson@umontreal.ca.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
authors.affiliation: Centre de recherche du Centre Hospitalier de l'Université de Montréal and Institut du cancer de Montréal, Montreal, Quebec, Canada. diane.provencher.chum@ssss.gouv.qc.ca.|Division de gynécologie oncologique Université de Montréal, Montreal, Quebec, Canada. diane.provencher.chum@ssss.gouv.qc.ca.
authors.forename: Diane
authors.initials: D
authors.lastname: Provencher
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada. patricia.tonin@mcgill.ca.|The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. patricia.tonin@mcgill.ca.|Departments of Medicine, McGill University, Montreal, Quebec, Canada. patricia.tonin@mcgill.ca.|Department of Medical Genetics, Montreal General Hospital, Room L10-132, 1650 Cedar Avenue, Montreal, Quebec, H3G 1A4, Canada. patricia.tonin@mcgill.ca.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Tonin
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D005260:Female; D018703:Founder Effect; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D011792:Quebec