title: Common BRCA2 variants and modification of breast and ovarian cancer risk in BRCA1 mutation carriers.
abstract: The HH genotype of the nonconservative amino acid substitution polymorphism N372H in the BRCA2 gene was reported to be associated with a 1.3- to 1.5-fold increase in risk of both breast and ovarian cancer. As these studies concerned sporadic cancer cases, we investigated whether N372H and another common variant located in the 5'-untranslated region (203G > A) of the BRCA2 gene modify breast or ovarian cancer risk in BRCA1 mutation carriers. The study includes 778 women carrying a BRCA1 germ-line mutation belonging to 403 families. The two BRCA2 variants were analyzed by the TaqMan allelic discrimination technique. Genotypes were analyzed by disease-free survival analysis using a Cox proportional hazards model. We found no evidence of a significant modification of breast cancer penetrance in BRCA1 mutation carriers by either polymorphism. In respect of ovarian cancer risk, we also saw no effect with the N372H variant but we did observe a borderline association with the 5'-untranslated region 203A allele (hazard ratio, 1.43; CI, 1.01-2.00). In contrast to the result of Healey et al. on newborn females and adult female controls, we found no departure from Hardy-Weinberg equilibrium in the distribution of N372H alleles for our female BRCA1 carriers. We conclude that if these single-nucleotide polymorphisms do modify the risk of cancer in BRCA1 mutation carriers, their effects are not significantly larger than that of N372H previously observed in the general population.
authors.affiliation: Unit of Genetic Epidemiology, IARC, 150, cours Albert-Thomas, 69372 Lyon cedex 08, France. hughes@iarc.fr
authors.forename: David J
authors.initials: DJ
authors.lastname: Hughes
authors.forename: Sophie M
authors.initials: SM
authors.lastname: Ginolhac
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coupier
authors.forename: Marilys
authors.initials: M
authors.lastname: Corbex
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bressac-de-Paillerets
authors.forename: Agnès
authors.initials: A
authors.lastname: Chompret
authors.forename: Yves-Jean
authors.initials: YJ
authors.lastname: Bignon
authors.forename: Nancy
authors.initials: N
authors.lastname: Uhrhammer
authors.forename: Christine
authors.initials: C
authors.lastname: Lasset
authors.forename: Sophie
authors.initials: S
authors.lastname: Giraud
authors.forename: Agnès
authors.initials: A
authors.lastname: Hardouin
authors.forename: Pascaline
authors.initials: P
authors.lastname: Berthet
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Peyrat
authors.forename: Joelle
authors.initials: J
authors.lastname: Fournier
authors.forename: Catherine
authors.initials: C
authors.lastname: Nogues
authors.forename: Rosette
authors.initials: R
authors.lastname: Lidereau
authors.forename: Danièle
authors.initials: D
authors.lastname: Muller
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fricker
authors.forename: Michel
authors.initials: M
authors.lastname: Longy
authors.forename: Christine
authors.initials: C
authors.lastname: Toulas
authors.forename: Rosine
authors.initials: R
authors.lastname: Guimbaud
authors.forename: Christine
authors.initials: C
authors.lastname: Maugard
authors.forename: Sylviane
authors.initials: S
authors.lastname: Olschwang
authors.forename: Drakoulis
authors.initials: D
authors.lastname: Yannoukakos
authors.forename: Francine
authors.initials: F
authors.lastname: Durocher
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Moisan
authors.forename: Jacques
authors.initials: J
authors.lastname: Simard
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mazoyer
authors.forename: Henry T
authors.initials: HT
authors.lastname: Lynch
authors.forename: Csilla
authors.initials: C
authors.lastname: Szabo
authors.forename: Gilbert M
authors.initials: GM
authors.lastname: Lenoir
authors.forename: David E
authors.initials: DE
authors.lastname: Goldgar
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.forename: Olga M
authors.initials: OM
authors.lastname: Sinilnikova
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics*; D002353:Carrier State; D005260:Female; D005787:Gene Frequency; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*; D011110:Polymorphism, Genetic; D012306:Risk