Mutation hotspots in cis-regulatory regions in cancer

In recent years, somatic mutations in cis-regulatory elements of cancer genomes have become a focus of much research. A landmark discovery occurred in 2013, in which recurrent somatic mutations were identified in the promoter of the key cancer-associated gene, TERT (reviewed in [1]). In the search for other highly recurrent cis-regulatory mutations which may serve as novel driver events, two papers, published in 2014 [2, 3], revealed somewhat surprising results. These studies investigated large cohorts of cancer genomes and found that, despite identifying many recurrent promoter mutations, few could be associated with gene expression changes. Of those that did alter gene expression, many of their target genes did not have strong links to cancer development. We also published similar unexpected findings in a genomewide survey of promoter mutations in the melanoma cellline, COLO829 [4]. The study showed that while some regulatory mutations can alter promoter activity (~17% of mutant promoter regions surveyed), one such mutation that was recurrent (~4.4%) in other melanomas was not associated with altered gene expression in actual cancer samples [4]. Remarkably, we additionally observed that of the 14 remaining promoter mutations surveyed to not alter promoter activity, five mutations were also recurrent in melanoma samples. Together these articles raised the question of why there are such high rates of recurrence among promoter mutations if many do not appear to arise due to their oncogenic ability to alter gene expression.