title: Familial risks, early-onset breast cancer, and BRCA1 and BRCA2 germline mutations.
abstract: BACKGROUND
  Having a family history of breast cancer, particularly if it involves early-onset disease, is a risk factor for breast cancer, but little is known about specific causes of this association. Consequently, we studied mothers, sisters, and aunts of an age-stratified sample of 1567 unselected case patients diagnosed with breast cancer before age 60 years, recruited to a population-based, case-control-family study, in which case patients, control subjects, and their relatives were administered the same questionnaire.
  
  
  METHODS
  Extensive BRCA1 and BRCA2 mutation testing was carried out for 788 case patients diagnosed before age 40 years, including manual sequencing of DNA from 72 patients with two or more affected relatives. Standardized morbidity ratios, age-specific cumulative risks, and hazard ratios were calculated for groupings of relatives.
  
  
  RESULTS
  Cumulative risks of breast cancer to age 50 years in the sisters, mothers, and aunts of the case patients, respectively, were 6, 3, and 2 times the population risk if the case patient was younger than age 40 years at diagnosis but were considerably lower if the case patient was older at diagnosis. When relatives of the case patients with a BRCA1 or BRCA2 mutation were excluded, these risks fell by, at most, 20%. Sisters and aunts, but not mothers, who had an additional first-degree relative with breast cancer were at increased risk, and the risk was greater when that relative was younger at diagnosis. Hazard ratios were 10.7 (95% confidence interval [CI] = 4.2 to 26.8) for sisters and 4.2 (95% CI = 2.2 to 8.1) for aunts, if the relative was aged 40 years at diagnosis. Fewer than one-third of the excess of breast cancers in relatives of case patients diagnosed before age 40 years that are attributed to familial factors are BRCA1- or BRCA2-related.
  
  
  CONCLUSIONS
  Mutations in genes other than BRCA1 and BRCA2 may be associated with a high risk of breast cancer, especially in young women.
authors.affiliation: Centre for Genetic Epidemiology, The University of Melbourne, Melbourne, Australia.
authors.forename: Gillian S
authors.initials: GS
authors.lastname: Dite
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.forename: Jane S
authors.initials: JS
authors.lastname: Hocking
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: Margaret R E
authors.initials: MR
authors.lastname: McCredie
authors.forename: Deon J
authors.initials: DJ
authors.lastname: Venter
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
mesh_terms: D000328:Adult; D017668:Age of Onset; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D016016:Proportional Hazards Models; D012306:Risk; D011795:Surveys and Questionnaires