The first wave of genome-wide association studies (GWAS) has lead to the discovery of many inherited, or germline, cancer-associated common genetic variants that now require basic biologic investigation. The majority of the GWAS association signals map to non-coding regions of the genome, but are located close to plausible candidate genes. Most regions identified thus far are specific to one type of cancer, though there are also several regions that point towards shared mechanisms across different types of cancers. Fine mapping of regions is required to identify the most promising candidate variants for follow-up studies using next generation sequencing approaches together with annotated datasets of common variants. The interrogation of GWAS signals requires extensive bioinformatic follow-up to prioritize variants, which may require consideration of unannotated transcripts, and regulatory elements, as well as functional elements for novel transcripts. Regulatory effects are queried with respect to the alteration of gene levels, epigenetics, and long-ranging effects on other genes at a distance.
My lab is investigating biologic mechanisms that could explain the direct association of variants with cancer susceptibility. Currently, effort is focused on regions that influence regulatory elements, either in close proximity to candidate genes, the impact of microRNAs (miRNA) variants acting upon fragile chromosomal sites, and epigenetic effects across multi-susceptibility regions.