Abstract
Recent genome-wide association studies (GWASs) have identified candidate genes contributing to cancer risk through low-penetrance mutations. Many of these genes were unexpected and, intriguingly, included well-known players in carcinogenesis at the somatic level. To assess the hypothesis of a germline-somatic link in carcinogenesis, we evaluated the distribution of somatic gene labels within the ordered results of a breast cancer risk GWAS. This analysis suggested frequent influence on risk of genetic variation in loci encoding for “driver kinases” (i.e., kinases encoded by genes that showed higher somatic mutation rates than expected by chance and, therefore, whose deregulation may contribute to cancer development and/or progression). Assessment of these predictions using a population-based case-control study in Poland replicated the association for rs3732568 in EPHB1 (odds ratio (OR) = 0.79; 95% confidence interval (CI): 0.63–0.98; Ptrend = 0.031). Analyses by early age at diagnosis and by estrogen receptor α (ERα) tumor status indicated potential associations for rs6852678 in CDKL2 (OR = 0.32, 95% CI: 0.10–1.00; Precessive = 0.044) and rs10878640 in DYRK2 (OR = 2.39, 95% CI: 1.32–4.30; Pdominant = 0.003), and for rs12765929, rs9836340, rs4707795 in BMPR1A, EPHA3 and EPHA7, respectively (ERα tumor status Pinteraction<0.05). The identification of three novel candidates as EPH receptor genes might indicate a link between perturbed compartmentalization of early neoplastic lesions and breast cancer risk and progression. Together, these data may lay the foundations for replication in additional populations and could potentially increase our knowledge of the underlying molecular mechanisms of breast carcinogenesis.
Highlights
With the advent of technical and methodological advances, several genome-wide association studies (GWASs) identifying common genetic variation associated with risk of developing cancer have been completed recently [1]
Analysis of the Cancer Genetic Markers of Susceptibility (CGEMS) GWAS dataset using the lowest genotypic P value per gene locus suggested true associations in genes annotated with Gene Ontology (GO) biological process terms linked to somatic events [26,27]
Since there is a positive correlation between the extension of a given locus and the number of single nucleotide polymorphisms (SNPs) it may contain, an unadjusted GWAS rank is biased at its lowest P values for specific processes in which large gene products frequently participate [26,28,29] (Fig. 1A)
Summary
With the advent of technical and methodological advances, several GWASs identifying common genetic variation associated with risk of developing cancer have been completed recently [1]. Illustrating the unbiased nature of GWASs, most hits have corresponded to a priori unexpected candidate genes In this context, the involvement of biological processes beyond the canonical DNA damage response in breast cancer is further suggested by the observed differential influence of low-penetrance risk alleles among BRCA1 and BRCA2 mutation carriers [7,8,9]. Common genetic variation in loci encoding for FGFR2 and MAP3K1 influences risk of breast cancer [2,4], and these genes were previously found to be somatically mutated in diverse neoplasias including breast cancer [10,11]. Additional breast cancer susceptibility loci have been described that include CDKN2A/B as candidates [15] While these observations suggest a ‘‘germlinesomatic’’ link in breast carcinogenesis, an analogous situation may exist for other neoplasias.
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