Common BRCA1 Variants and Susceptibility to Breast and Ovarian Cancer in the General Population

Abstract

Most multiple case families of young onset breast cancer and ovarian cancer are thought to be due to highly penetrant mutations in the predisposing genes BRCA1 and BRCA2. However, these mutations are uncommon in the population and they probably account for only a few percent of all breast cancer incidence. A much larger fraction of breast cancer might, in principle, be due to common variants which confer more modest individual risks. There are several common polymorphisms in the BRCA1 gene which generate amino acid substitutions. We have examined the frequency of four of these polymorphisms: Gln356Arg, Pro871Leu, Glu1038Gly and Ser1613Gly in large series of breast and ovarian cancer cases and matched controls. Due to strong linkage disequilibrium, these four sites generate only three haplotypes with a frequency > 1.3%. The most common haplotypes, defined by the alleles Gln356Pro871Glu1038Ser1613 and Gln356Leu871Gly1038Gly1613, have frequencies of 0.57 and 0.32 respectively, and these frequencies do not differ significantly between patient and control groups. Thus the most common polymorphisms of the BRCA1 gene do not make a significant contribution to breast or ovarian cancer risk. However, our data suggest that the Arg356 allele may have a different genotype distribution in breast cancer patients from that in controls (Arg356 homozygotes are more frequent in the control groups, P = 0.01), indicating that it may be protective against breast cancer. If this finding can be confirmed, it may provide an insight into the structural features of the BRCA1 protein that are important for its function.

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.…”

“…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. In our population from Tyrol, the homozygotes were found in the same ratio in both the control and the patient groups.…”

“…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).…”

“…Searching the literature, no association with breast cancer has been found for Q356R and P871L (BRCA1), although the authors claimed that being homozygous for 356R might protect against breast cancer (Dunning et al, 1997). 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 role of extreme phenotype selection studies in the identification of clinically relevant genotypes in cancer research

“…47 Finally, some histocompatibility antigen alleles have been linked in case-control studies with a decreased susceptibility to lung carcinoma, 48 melanoma, 49 and renal cell carcinoma, 50 and even homozygotic women for determined polymorphic alleles of the BRCA-1 gene have been associated with a decreased risk of breast carcinoma. 51 The ambiguous and clinically not very relevant results of some of these studies may be explained by flaws in methodology, as detailed elsewhere, 27 but also may be related in part to an inadequate selection of the study populations. Compared with the former studies, in which individuals were selected by a very characteristic phenotype-a definite protection against developing HIV or myocardial infarction-the latter studies compared the risk of patients who have developed disease with a control group formed by normal control participants.…”