Non-coding genetic variation in cancer

The vast majority of somatic variants in cancer genomes occur in non-coding regions. However, progress in cancer genomics in the past decades has been mostly focused on coding regions, largely due to the prohibitive cost of whole genome sequencing. Recent technological advances have decreased sequencing costs leading to the current acquisition of thousands of tumor whole genomes, which has led to a hunt for non-coding drivers. The most well characterized regulatory drivers are in the TERT promoter and have been identified in many cancer types. Despite the larger fraction of somatic variants occurring in non-coding regions, the number of non-coding drivers identified so far is much less than the number of coding region drivers. Here we discuss the reasons that may hinder the detection of non-coding drivers. We also examine the relationship between non-coding genetic variation and epigenetic state in tumor cells and assert the need for additional epigenetic data sets as a prerequisite for understanding the rewiring of regulatory networks in cancer.