Localization of breast cancer susceptibility loci by genome‐wide SNP linkage disequilibrium mapping

Abstract

We studied the feasibility of a novel approach to localize breast cancer susceptibility genes, using a low-density genomewide panel of single-nucleotide polymorphisms and taking advantage of large regions of linkage disequilibrium (LD) flanking Jewish disease genes in high-risk cases. With Affymetrix GeneChip arrays, we genotyped 8,576 polymorphisms in three sets of Ashkenazi Jewish breast cancer cases: a ''validation'' set of 27 breast cancer cases, all of whom carried the BRCA2*6174delT founder mutation; a ''field'' set of 19 breast cancer cases from male breast cancer kindreds, which simulated conditions for finding new genes; and a ''test'' set of 57 probands from breast cancer kindreds (4 or more cases/ kindred), in which mutations in BRCA1 and BRCA2 had been excluded. To identify associations, we compared the frequency of genotypes and haplotypes in cases vs. controls by the Fisher's exact test and a maximum likelihood ratio test. In the ''validation'' set, we demonstrated the presence of a region of linkage disequilibrium on BRCA2*6174delT chromosomes that spanned over 5 million bases. In the ''field'' set, we showed that this large region of linkage disequilibrium flanking BRCA2 was detectable despite the presence of heterogeneity in the sample set. Finally, in the ''test'' set, at least three regions of interest emerged that could contain novel breast cancer genes, one of which had been identified previously by linkage analysis. While these results demonstrate the feasibility of genome-wide association strategies, further application of this approach will critically depend on optimizing the density and distribution of SNPs and the size and type of study design. Genet. Epidemiol. 30:48-61, 2006. r 2005 Wiley-Liss, Inc.

Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33

“…Compared with the study of Easton (18), where 390 familial breast cancer cases were screened with 227,876 SNPs, here, we used 249 familial breast cancer cases at approximately the same SNP density. In contrast to the Easton study, this study was performed on a relatively isolated population, AJs, in which we have demonstrated a significant increase in power to detect founder mutations in other genes (20). A principal components analysis (PCA) was also applied as an exclusion criteria for the familial study, in contrast to genomic control or a statistical-significance adjustment criterion method.…”

“…These studies have implicated a locus near FGFR2 as associated with an Ϸ1.2-fold increased risk of the disease. To add to the potential power of the GWAS approach, we have proposed and validated the use of a genetic isolate, in which larger regions of linkage disequilibrium surrounding known and putative ''founder'' mutations should increase the ability to map previously unidentified loci (20). As a first test of this approach, we have performed a GWAS study with 249 Ashkenazi Jewish (AJ) kindreds containing multiple cases of breast cancer but lacking BRCA1 or BRCA2 mutations and then replicated our findings in an independently ascertained cohort of nearly 1,000 AJ breast cancer cases and matched AJ controls.…”

Hierarchical Bayes prioritization of marker associations from a genome‐wide association scan for further investigation

“…Several such studies are underway [Thomas et al, 2005] and a few have already been published [Ozaki et al, 2002;Maraganore et al, 2005;Shiffman et al, 2005;Duerr et al, 2006;Ellis et al, 2006;Bierut et al, 2007;Gudmundsson et al, 2007;Riley et al, 2007;Rioux et al, 2007;Sladek et al, 2007;Spinola et al, 2007;Yeager et al, 2007]. Most of the studies currently underway have adopted some form of multistage design [Satagopan and Elston, 2003], typically entailing genotyping some proportion of the sample using the entire array of SNPs and then genotyping only some subset of the most ''promising'' associations on the remaining subjects.…”

Hereditary breast cancer: new genetic developments, new therapeutic avenues

“…ModiWer genes could independently act as low penetrance genes for breast cancer susceptibility and, in the past two years, numerous genome-wide association studies have looked at breast cancer susceptibility, and have identiWed new loci such as FGFR2 (see Table 2 and Antoniou et al 2008;Easton et al 2007;Ellis et al 2006;Gold et al 2008;Huijts et al 2007;Hunter et al 2007;Murabito et al 2007;Stacey et al 2007Stacey et al , 2008. Other individuals looked at a few single nucleotide polymorphisms (SNPs) in large cohorts (Cox et al 2007a, b).…”