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Mutations in  BRCA1  and  BRCA2  confer a high risk of breast cancer (BC), but the magnitude of this risk seems to vary according to the study and various factors. Although controversial, there are data to support the hypothesis of allelic risk heterogeneity.    Methods  We assessed variation in BC risk according to factors related to pregnancies by location of mutation in the homogeneous risk region of  BRCA1  and  BRCA2  in 990 women in the French study GENEPSO by using a weighted Cox regression model.    Results  Our results confirm the existence of the protective effect of an increasing number of full-term pregnancies (FTPs) toward BC among  BRCA1  and  BRCA2  mutation carriers (≥3 versus 0 FTPs: hazard ratio (HR) = 0.51, 95% confidence interval (CI) = 0.33 to 0.81). Additionally, the HR shows an association between incomplete pregnancies and a higher BC risk, which reached 2.39 (95% CI = 1.28 to 4.45) among women who had at least three incomplete pregnancies when compared with women with zero incomplete pregnancies. This increased risk appeared to be restricted to incomplete pregnancies occurring before the first FTP (HR = 1.77, 95% CI = 1.19 to 2.63). We defined the TMAP score (defined as the Time of Breast Mitotic Activity during Pregnancies) to take into account simultaneously the opposite effect of full-term and interrupted pregnancies. Compared with women with a TMAP score of less than 0.35, an increasing TMAP score was associated with a statistically significant increase in the risk of BC ( P  trend = 0.02) which reached 1.97 (95% CI = 1.19 to 3.29) for a TMAP score >0.5 (versus TMAP ≤0.35). All these results appeared to be similar in  BRCA1  and  BRCA2 . Nevertheless, our results suggest a variation in BC risk associated with parity according to the location of the mutation in  BRCA1 . Indeed, parity seems to be associated with a significantly decreased risk of BC only among women with a mutation in the central region of  BRCA1  (low-risk region) (≥1 versus 0 FTP: HR = 0.27, 95% CI = 0.13 to 0.55) ( P  interaction  <10 -3 ).    Conclusions  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 BC.

breast cancer research

Variation in breast cancer risk associated with factors related to pregnancies according to truncating mutation location, in the French National BRCA1 and BRCA2 mutations carrier cohort (GENEPSO)