title: Proven non-carriers in BRCA families have an earlier age of onset of breast cancer.
abstract: BACKGROUND
  Risk estimates for proven non-carriers in BRCA mutation families are inconsistent for breast cancer and lacking for ovarian cancer. We aimed to assess the age-related risks for breast and ovarian cancer for proven non-carriers in these families.
  
  
  METHODS
  A consecutive cohort study ascertained 464 proven non-carriers who had a first-degree relative with a pathogenic BRCA mutation. Kaplan-Meier analyses were used to estimate the age-related cancer risks, and we calculated standardised incidence ratios.
  
  
  RESULTS
  In the 464 non-carriers, 17 breast cancers and two ovarian cancers were detected at a mean age of 47 years (95% confidence interval (CI) 32-61) and 49 years (95% CI 32-67), respectively. Overall, by the age of 50, the breast and ovarian cancer risks among non-carriers were 6.4% (95% CI 2.9-9.8%) and 0.4% (95% CI 0-1.3%), of which the breast cancer risk was statistically significantly higher than the risk in the general population. In particular, the number of breast cancers among non-carriers in BRCA1 families was higher than expected for the general population (standardised incidence ratio (SIR) 2.0, 95% CI 1.1-3.3). In the BRCA1 cohort, the mean number of breast cancer cases was higher in families in which non-carriers were diagnosed before the age of 50 (p=0.04).
  
  
  CONCLUSIONS
  The age at diagnosis of breast cancer in non-carriers in BRCA mutation families is younger than expected, yielding an increased risk in the fifth decade. This effect is most evident in BRCA1 families. If our results are confirmed by others, this could affect the advice given on breast cancer screening to proven non-carriers between the age of 40 and 50 in such families.
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: j.r.vos01@umcg.nl.
authors.forename: Janet R
authors.initials: JR
authors.lastname: Vos
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Geertruida H
authors.initials: GH
authors.lastname: de Bock
authors.affiliation: Department of Gynecologic Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Natalia
authors.initials: N
authors.lastname: Teixeira
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Dorina M
authors.initials: DM
authors.lastname: van der Kolk
authors.affiliation: Department of Surgical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Jansen
authors.affiliation: Department of Gynecologic Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Marian J E
authors.initials: MJ
authors.lastname: Mourits
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jan C
authors.initials: JC
authors.lastname: Oosterwijk
mesh_terms: D000328:Adult; D017668:Age of Onset; D001943:Breast Neoplasms / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree; D012307:Risk Factors