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).

Julie Lecarpentier,Olivier Caron,Nadine Andrieu,Pascaline Berthet,Laurence Faivre,Valérie Bonadona,Jean-Pierre Fricker,Catherine Noguès,François Eisinger,Chrystelle Colas,Paul Gesta,Emmanuelle Mouret-Fourme,Rosette Lidereau,Catherine Dugast,Alain Lortholary,Pascal Pujol,Julie Tinat,Isabelle Coupier,Michel Longy,Christine Lasset,Dominique Stoppa‐Lyonnet ,É Luporsi ,Benedetto Bruno ,Marion Gauthier‐Villars ,Marc Frénay,L Gladieff

doi:10.1186/bcr3218

Abstract

IntroductionMutations 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.MethodsWe 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.ResultsOur 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) (Pinteraction <10-3).ConclusionsOur 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.

Highlights

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
Many studies have established that women who had their first full-term pregnancy (FTP) at a young age have a lower risk of BC than nulliparous women or women who had their first FTP when they were older than 30 years of age; additional pregnancies are associated with even lower risks
To assess the variation of BC risk associated with pregnancies and breast-feeding by location of truncating mutations in BRCA1 and BRCA2, we used regions previously defined as homogeneous in BC risk by Lecarpentier et al We considered two groups of mutation in BRCA1, those located in low-risk region in BRCA1 (LR1) and those located outside LR1

Summary

Introduction

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. Carriers of mutations in the BRCA1 and BRCA2 genes are at very high risk of developing breast cancer (BC) and ovarian cancer. Estimates of the lifetime risk of developing BC for BRCA1 and BRCA2 mutation carriers range from 30% to 80% and from 9% to 84%, respectively [1]. Incomplete penetrance and the range of these risk estimates suggest the existence within families of genetic or shared environmental or lifestyle factors that modify the risk of BC. Controversial conclusions have been drawn from studies that have examined the risk of BC associated with incomplete pregnancies. While some older studies found a possible positive association between interrupted pregnancies and BC risk [5,6,7,8,9], the most recent meta-analyses concluded that an increased number of either spontaneous or induced abortions was not associated with an increased BC risk [10,11,12]

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