title: 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).
abstract: BACKGROUND
  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) (Pinteraction <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.
authors: Julie
authors: J
authors: Lecarpentier
authors: Catherine
authors: C
authors: Noguès
authors: Emmanuelle
authors: E
authors: Mouret-Fourme
authors: Marion
authors: M
authors: Gauthier-Villars
authors: Christine
authors: C
authors: Lasset
authors: Jean-Pierre
authors: JP
authors: Fricker
authors: Olivier
authors: O
authors: Caron
authors: Dominique
authors: D
authors: Stoppa-Lyonnet
authors: Pascaline
authors: P
authors: Berthet
authors: Laurence
authors: L
authors: Faivre
authors: Valérie
authors: V
authors: Bonadona
authors: Bruno
authors: B
authors: Buecher
authors: Isabelle
authors: I
authors: Coupier
authors: Laurence
authors: L
authors: Gladieff
authors: Paul
authors: P
authors: Gesta
authors: François
authors: F
authors: Eisinger
authors: Marc
authors: M
authors: Frénay
authors: Elisabeth
authors: E
authors: Luporsi
authors: Alain
authors: A
authors: Lortholary
authors: Chrystelle
authors: C
authors: Colas
authors: Catherine
authors: C
authors: Dugast
authors: Michel
authors: M
authors: Longy
authors: Pascal
authors: P
authors: Pujol
authors: Julie
authors: J
authors: Tinat
authors: Rosette
authors: R
authors: Lidereau
authors: Nadine
authors: N
authors: Andrieu
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics*; D012306:Risk; D055815:Young Adult