Breast cancer is the most frequent and mortal cancer among French women. Mutations in BRCA1 and BRCA2 confer a high risk of breast cancer. The diversity of BRCA1 and BRCA2 mutations and of gyneco-obstetrical and life style risk factors may modify the magnitude of this risk. The objective of this study is to assess breast cancer risk taking into account gyneco-obstetrical and life style factors, location of mutation in BRCA1 and BRCA2 genes and there potential interaction.The data from 1337 women BRCA1 and BRCA2 mutation carriers of the French study GENEPSO have been analysed by using a weighted Cox regression model to take into account the bias of recruitment. Our results show an association between breast cancer risk and X-ray exposures, tobacco, body mass index, age at menarche, parity, interrupted pregnancies, oral contraceptives, menopausal status and hormone replacement therapy. We confirm the existence of a central low breast cancer risk region in BRCA1 (LR1 region between codons 374 and 1161) and in BRCA2 (LR2 region between codons 957 and 1827). In addition, a new high breast cancer risk region is found in the 3’ region of BRCA2 (HR2 region between codons 2546 and 2968). Moreover, our results suggest a variation in breast cancer risk associated with parity and menopausal status according to the location of the mutation in BRCA1 and BRCA2. Our findings show that, taking into account environmental and lifestyle modifiers, mutation position might be important for the clinical management of BRCA1 and BRCA2 mutation carriers and could also be helpful in understanding how BRCA1 and BRCA2 genes are involved in breast cancer.
