title: Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study.
abstract: BACKGROUND
  Several of the known risk factors for ovarian cancer are thought to act through their effects on ovulation and the menstrual cycle, such as parity, breastfeeding, and use of oral contraceptives. We aimed to assess the effect of these three risk factors, and of tubal ligation, on the risk of ovarian cancer in women who carry a mutation in the BRCA1 or BRCA2 genes.
  
  
  METHODS
  We did a matched case-control study in women who were found to carry a pathogenetic mutation in BRCA1 or BRCA2. Participants were derived from a population-based study of ovarian cancer in Ontario, Canada, and from an international registry of mutation carriers based in Toronto, ON, Canada. All participants completed a written questionnaire that detailed their reproductive history. Women with invasive ovarian cancer and controls were matched on year of birth, country of residence, mutation (BRCA1 or BRCA2), and history of breast cancer. The odds ratios and 95% CI for ovarian cancer were estimated with respect to use of oral contraceptives, parity, breastfeeding, and tubal ligation.
  
  
  RESULTS
  Questionnaires were completed by 799 women with a history of invasive ovarian cancer (670 with BRCA1 mutations, 128 with BRCA2 mutations, and one with a mutation in both genes), and controls were 2424 women without ovarian cancer (2043 with BRCA1 mutations, 380 with BRCA2 mutations, and one with a mutation in both genes). Use of oral contraceptives reduced the risk of ovarian cancer in carriers of BRCA1 mutations (odds ratio 0.56 [95% CI 0.45-0.71]; p<0.0001) and carriers of BRCA2 mutations (0.39 [0.23-0.66]; p=0.0004). Parity was associated with a reduced risk for carriers of BRCA1 mutations (0.67 [0.46-0.96]; p=0.03), but with an increased risk for those with BRCA2 mutations (2.74 [1.18-6.41]; p=0.02). Breastfeeding was associated with a reduced risk for carriers of BRCA1 mutations (0.74 [0.56-0.97]; p=0.03). An effect of similar magnitude was seen for carriers of BRCA2 mutations (0.72 [0.41-1.29]; p=0.27), but this was not statistically significant. The association with tubal ligation was not significant for carriers of BRCA1 mutations (0.80 [0.59-1.08]; p=0.15), or for carriers of BRCA2 mutations (0.63 [0.34-1.15]; p=0.13).
  
  
  CONCLUSIONS
  Oral contraceptives could be used as a means to prevent ovarian cancer in carriers of BRCA1 and BRCA2 mutations. The possible adverse effect of parity on ovarian-cancer risk in women with a BRCA2 mutation needs further study.
authors.affiliation: Samuel Lunenfeld Research Institute, Toronto, ON, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: McLaughlin
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Risch
authors.forename: Jan
authors.initials: J
authors.lastname: Lubinski
authors.forename: Pal
authors.initials: P
authors.lastname: Moller
authors.forename: Parviz
authors.initials: P
authors.lastname: Ghadirian
authors.forename: Henry
authors.initials: H
authors.lastname: Lynch
authors.forename: Beth
authors.initials: B
authors.lastname: Karlan
authors.forename: David
authors.initials: D
authors.lastname: Fishman
authors.forename: Barry
authors.initials: B
authors.lastname: Rosen
authors.forename: Susan L
authors.initials: SL
authors.lastname: Neuhausen
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.forename: Noah
authors.initials: N
authors.lastname: Kauff
authors.forename: Susan
authors.initials: S
authors.lastname: Domchek
authors.forename: Nadine
authors.initials: N
authors.lastname: Tung
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
authors.forename: William
authors.initials: W
authors.lastname: Foulkes
authors.forename: Ping
authors.initials: P
authors.lastname: Sun
authors.forename: Steven A
authors.initials: SA
authors.lastname: Narod
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics / Q000517:prevention & control; D016022:Case-Control Studies; D003278:Contraceptives, Oral, Hormonal / Q000008:administration & dosage*; D005260:Female; D006579:Heterozygote; D006801:Humans; D016555:Matched-Pair Analysis; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics / Q000517:prevention & control*; D012307:Risk Factors; D013997:Time Factors
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D003278:Contraceptives, Oral, Hormonal