Abstract
BackgroundRecent advances in whole-genome association studies (WGASs) for human cancer risk are beginning to provide the part lists of low-penetrance susceptibility genes. However, statistical analysis in these studies is complicated by the vast number of genetic variants examined and the weak effects observed, as a result of which constraints must be incorporated into the study design and analytical approach. In this scenario, biological attributes beyond the adjusted statistics generally receive little attention and, more importantly, the fundamental biological characteristics of low-penetrance susceptibility genes have yet to be determined.MethodsWe applied an integrative approach for identifying candidate low-penetrance breast cancer susceptibility genes, their characteristics and molecular networks through the analysis of diverse sources of biological evidence.ResultsFirst, examination of the distribution of Gene Ontology terms in ordered WGAS results identified asymmetrical distribution of Cell Communication and Cell Death processes linked to risk. Second, analysis of 11 different types of molecular or functional relationships in genomic and proteomic data sets defined the "omic" properties of candidate genes: i/ differential expression in tumors relative to normal tissue; ii/ somatic genomic copy number changes correlating with gene expression levels; iii/ differentially expressed across age at diagnosis; and iv/ expression changes after BRCA1 perturbation. Finally, network modeling of the effects of variants on germline gene expression showed higher connectivity than expected by chance between novel candidates and with known susceptibility genes, which supports functional relationships and provides mechanistic hypotheses of risk.ConclusionThis study proposes that cell communication and cell death are major biological processes perturbed in risk of breast cancer conferred by low-penetrance variants, and defines the common omic properties, molecular interactions and possible functional effects of candidate genes and proteins.
Highlights
Recent advances in whole-genome association studies (WGASs) for human cancer risk are beginning to provide the part lists of low-penetrance susceptibility genes
The key to this study was the public availability of the landmark WGAS for breast cancer risk released by the Cancer Genetic Markers of Susceptibility (CGEMS) initiative [2]
We analyzed the results of this WGAS alongside various omic data sets of breast cancer and normal cellular conditions, following a biology-driven strategy based on the asymmetrical representation of biological information in ordered gene lists (Figure 1)
Summary
Recent advances in whole-genome association studies (WGASs) for human cancer risk are beginning to provide the part lists of low-penetrance susceptibility genes. Statistical analysis in these studies is complicated by the vast number of genetic variants examined and the weak effects observed, as a result of which constraints must be incorporated into the study design and analytical approach In this scenario, biological attributes beyond the adjusted statistics generally receive little attention and, more importantly, the fundamental biological characteristics of low-penetrance susceptibility genes have yet to be determined. As a result of this progress, the last year has seen a spectacular increase in the number of published studies in which these types of variants or single nucleotide polymorphisms (SNPs) are detected Projects such as the National Cancer Institute's Cancer Genetic Markers of Susceptibility (CGEMS) and work carried out by deCODE Genetics and the Breast Cancer Association Consortium have produced partial lists of the risk variants of different cancer types in diverse populations [2,3,4]. As a result of these complications, the findings cannot be considered true positives until they have been replicated in an independent, preferentially larger-scale study [13,14]
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