title: Variation in breast cancer risk with mutation position, smoking, alcohol, and chest X-ray history, in the French National BRCA1/2 carrier cohort (GENEPSO).
abstract: Germline mutations in BRCA1/2 confer a high risk of breast cancer (BC), but the magnitude of this risk varies according to various factors. Although controversial, there are data to support the hypothesis of allelic-risk heterogeneity. We assessed variation in BC risk according to the location of mutations recorded in the French study GENEPSO. Since the women in this study were selected from high-risk families, oversampling of affected women was eliminated by using a weighted Cox-regression model. Women were censored at the date of diagnosis when affected by any cancer, or the date of interview when unaffected. A total of 990 women were selected for the analysis: 379 were classified as affected, 611 as unaffected. For BRCA1, there was some evidence of a central region where the risk of BC is lower (codons 374-1161) (HR = 0.59, P = 0.04). For BRCA2, there was a strong evidence for a region at decreased risk (codons 957-1827) (HR = 0.35, P = 0.005) and for one at increased risk (codons 2546-2968) (HR = 3.56, P = 0.01). Moreover, we found an important association between radiation exposure from chest X-rays and BC risk (HR = 4.29, P < 10(-3)) and a positive association between smoking more than 21 pack-years and BC risk (HR = 2.09, P = 0.04). No significant variation in BC risk associated with chest X-ray exposure, smoking, and alcohol consumption was found according to the location of the mutation in BRCA1 and BRCA2. Our findings are consistent with those suggesting that the risk of BC is lower in the central regions of BRCA1/2. A new high-risk region in BRCA2 is described. Taking into account environmental and lifestyle modifiers, the location of mutations might be important in the clinical management of BRCA mutation carriers.
authors.affiliation: Institut National de Santé et de Recherche Médicale, Unité U900, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Lecarpentier
authors.forename: Catherine
authors.initials: C
authors.lastname: Noguès
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Mouret-Fourme
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.forename: Christine
authors.initials: C
authors.lastname: Lasset
authors.forename: Olivier
authors.initials: O
authors.lastname: Caron
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fricker
authors.forename: Laurence
authors.initials: L
authors.lastname: Gladieff
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.forename: Hagay
authors.initials: H
authors.lastname: Sobol
authors.forename: Paul
authors.initials: P
authors.lastname: Gesta
authors.forename: Marc
authors.initials: M
authors.lastname: Frenay
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Luporsi
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coupier
authors.forename: Rosette
authors.initials: R
authors.lastname: Lidereau
authors.forename: Nadine
authors.initials: N
authors.lastname: Andrieu
mesh_terms: D000328:Adult; D000368:Aged; D000428:Alcohol Drinking; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D012306:Risk; D012907:Smoking; D014965:X-Rays; D055815:Young Adult