Dissecting genetic risk factors in breast cancer

Breast cancer associated with germline pathogenic variants in BRCA1 or BRCA2 is recognized for its strong familial risk [1]. In addition to these BRCA1 and BRCA2 variants, other rare (allele frequency < 0.005) highly penetrant variants in TP53, PTEN, and ATM account for ~25% of breast cancer familial risk [2]. Other susceptibility genes have been identified (PALB2, CHEK2, RECQL, NBN) as well as a large number of low penetrance variants [[3] and references therein]. However, known variants account for only ~50% of breast cancer susceptibility illustrating the polygenic nature of breast cancer risk and indicating that variants contributing to breast cancer risk remain to be discovered [4]. Genome Wide Association Studies (GWAS) serve as a powerful approach for discovering common risk variants underlying disease etiology. Often these variants reside within the non-coding region of the genome making the determination of functional mechanisms driving susceptibility a challenging task [5]. Differences in expression due to common polymorphic alleles have been shown to affect a variety of phenotypes involved in human diseases as well as account for 30% of cis-regulation of genes [6]. In the recent study published by Oncotarget, Hamdi et al. exploited this concept to search for additional breast cancer susceptibility loci [8]. In the study, Hamdi et al. evaluated 313 SNPs in 175 genes related to cancer for association with breast cancer risk in 46,451 breast cancer cancers and 42,599 controls of Caucasian ancestry participating in the Breast Cancer Association Consortium (BCAC) genotyped using the custom Illumina Infinium array iCOGS (Figure 1). First, the authors generated a list of genes implicated in cancer pathways using Kyoto Encyclopedia of Genes and Genomes (KEGG), a database which links genomic to functional information, and published data. Then, variants within these gene regions which had been previously