Cancer regulatory variation

The search for somatic cancer driver genes has largely focused on variants altering protein-coding regions of the genome but as this search has plateaued, there has been increasing interest in understanding how the non-coding portion of the genome regulates genes important for carcinogenesis. The increasing number of tumor whole genome sequences has fueled discoveries of recurrent gene regulatory mutations or ‘hotspots’ and has provided a comprehensive look at structural variants. One recurrent ‘hotspot’ is the TERT promoter region which exemplifies the variety of non-coding variants that can occur including simple somatic mutations, ‘enhancer hijacking’, copy number and neutral alterations, and insertion of transposable elements and viral enhancers. Integration of multiple omics datasets and functional assays are imperative for linking variants with functional effects.