A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability

Abstract

Inherited mutations in the gene BRCA2 predispose carriers to early onset breast cancer, but such mutations account for fewer than 2% of all cases in East Anglia. It is likely that low penetrance alleles explain the greater part of inherited susceptibility to breast cancer; polymorphic variants in strongly predisposing genes, such as BRCA2, are candidates for this role. BRCA2 is thought to be involved in DNA double strand break-repair. Few mice in which Brca2 is truncated survive to birth; of those that do, most are male, smaller than their normal littermates and have high cancer incidence. Here we show that a common human polymorphism (N372H) in exon 10 of BRCA2 confers an increased risk of breast cancer: the HH homozygotes have a 1.31-fold (95% CI, 1.07-1.61) greater risk than the NN group. Moreover, in normal female controls of all ages there is a significant deficiency of homozygotes compared with that expected from Hardy-Weinberg equilibrium, whereas in males there is an excess of homozygotes: the HH group has an estimated fitness of 0.82 in females and 1.38 in males. Therefore, this variant of BRCA2 appears also to affect fetal survival in a sex-dependent manner.

Association of NQO1 polymorphism with spontaneous breast cancer in two independent populations

“…The investigated SNPs in BRCA1 and BRCA2 showed no association with breast cancer in the two populations from Austria and the Czech Republic. This is in agreement with previous results for the P871L polymorphism (Dunning et al, 1997), but there are discrepancies for the Q356R polymorphism in BRCA1 (Dunning et al, 1997) and the N372H polymorphism in BRCA2 (Healey et al, 2000). One paper (Dunning et al, 1997) claimed a protective effect for the R356 allele in the homozygous state.…”

“…No significant difference was observed between cases and controls when we compared frequencies of heterozygotes, both P187S and R72P, and of homozygotes for the common allele, P187 and R72, respectively. We also analysed the H372 H polymorphism in the BRCA2 gene to test for a previously found association with gender (Healey et al, 2000) in 2442 controls (1530 men and 912 women). No difference of genotype frequencies between men and women (P ¼ 0.73) was found and also no deviation from expected frequencies assuming Hardy -Weinberg equilibrium (P ¼ 0.99).…”

“…BRCA1 and BRCA2 are the well-established susceptibility genes for familial breast cancer (Dunning et al, 1997(Dunning et al, , 2001Healey et al, 2000;Nathanson and Weber, 2001;Goode et al, 2002), TP53 is a gene involved in apoptosis (Dumont et al, 2003), ApoE influences lipid metabolism and cardiovascular disease (Menzel et al, 1983) and may be involved in tumour proliferation (Moysich et al, 2000;Zunarelli et al, 2000), NQO1 is engaged in carcinogen metabolism (Nebert et al, 2002) and GNB3 is part of a signal transduction pathway (Siffert et al, 1998).…”

“…In case of the 372H allele (BRCA2), an increased risk for developing breast cancer has been observed (Healey et al, 2000) together with an association with foetal survival. The 72P allele of the polymorphism in TP53 was only weakly associated with an increased risk for breast cancer (Nathanson and Weber, 2001).…”

Interactions between genetic and reproductive factors in breast cancer risk in a population‐based sample of African‐American families

“…However, the protective effect of spontaneous abortions may involve other factors, for example, those associated with fertility, because this effect was not observed for induced abortions. Interestingly, a recent study found that a common variant in the BRCA2 gene was associated with both BC risk and fetal survival [Healey et al, 2000]. There is now accumulating evidence that, besides BRCA1 and BRCA2, other genetic and environmental factors are likely to be involved in familial BC risk.…”