Deep targeted sequencing of 12 breast cancer susceptibility regions in 4611 women across four different ethnicities

Abstract

BackgroundAlthough genome-wide association studies (GWASs) have identified thousands of disease susceptibility regions, the underlying causal mechanism in these regions is not fully known. It is likely that the GWAS signal originates from one or many as yet unidentified causal variants.MethodsUsing next-generation sequencing, we characterized 12 breast cancer susceptibility regions identified by GWASs in 2288 breast cancer cases and 2323 controls across four populations of African American, European, Japanese, and Hispanic ancestry.ResultsAfter genotype calling and quality control, we identified 137,530 single-nucleotide variants (SNVs); of those, 87.2 % had a minor allele frequency (MAF) <0.005. For SNVs with MAF >0.005, we calculated the smallest number of SNVs needed to obtain a posterior probability set (PPS) such that there is 90 % probability that the causal SNV is included. We found that the PPS for two regions, 2q35 and 11q13, contained less than 5 % of the original SNVs, dramatically decreasing the number of potentially causal SNVs. However, we did not find strong evidence supporting a causal role for any individual SNV. In addition, there were no significant gene-based rare SNV associations after correcting for multiple testing.ConclusionsThis study illustrates some of the challenges faced in fine-mapping studies in the post-GWAS era, most importantly the large sample sizes needed to identify rare-variant associations or to distinguish the effects of strongly correlated common SNVs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0772-7) contains supplementary material, which is available to authorized users.

Refining the genetic risk of breast cancer with rare haplotypes and pattern mining

“…But this model fails to account for the lack of rare variants discovered so far in the vicinity of breast cancer-risk GWAS hits ( Lindström et al, 2016 ; Li et al, 2018 ) and the comparatively few mutations identified by linkage analysis and subsequent positional cloning ( Gonzalez-Neira et al, 2007 ; Rosa-Rosa et al, 2009a ). An alternative hypothesis is that the haplotype itself is the rare causal variant and that risk is because of the interaction of alleles at discrete locations along the haplotype.…”

Potential Misrepresentation of Inherited Breast Cancer Risk by Common Germline Alleles

“…It is, however, also possible that the rare haplotypes do not represent single risk mutations, but rare combinations of alleles whose interaction predisposes to disease. Few rare single variants have been found to explain synthetic associations of GWAS hits at breast cancer loci (11,12). Furthermore, despite the prevalence of GWAS hits, comparatively few rare mutations have been found in family-based linkage studies of breast cancer with subsequent positional cloning (33,34).…”

“…One is the hypothesis that so-called "synthetic associations" of rare variants near GWAS hits explain observed GWAS signals (8). While theoretical and sequencing studies have not provided strong evidence for this hypothesis (9)(10)(11)(12), it has not been considered whether rare haplotypes, instead of rare variants, underlie GWAS hits. Another hypothesis is that human diseases have substantial "genetic heterogeneity," being due primarily to rare mutations, such as those of the BRCA1/2 genes, which segregate in families (13).…”

Novel applications of next-generation sequencing in breast cancer research

“…Breast cancer is one of the most common cancers in human beings, and the incidence among women is the first. 1 So far, the incidence of breast cancer has accounted for 30% of female malignant tumor. 2 Breast cancer is the most common cancer among women of the western developed countries, while it is also increasing yearly in developing countries.…”