Regulatory Site Mutations Undergo Positive Selection in Cancer

As more whole-genome sequencing data are collected from human tumors, it is becoming possible to analyze mutations in noncoding regions. Melton and colleagues integrated whole-genome sequencing data from 436 patients across 8 cancer types in The Cancer Genome Atlas with annotated known and predicted regulatory sites from the Encyclopedia of DNA Elements and other databases to identify recurrent point mutations in regulatory elements. Whereas coding exon mutations accounted for less than 1% of mutations in a given cancer type, mutations in putative regulatory elements accounted for 31% to 39% of all mutations, raising the possibility that aberrant function of regulatory elements may be a significant driving force in tumorigenesis. These regulatory regions did not have a lower mutation rate than regions with similar genomic features, which would be expected to be the case if regulatory site mutations were deleterious to cancer cells and subject to negative selection. Instead, several mutation categories were enriched among the mutations identified, indicative of positive selection. Some mutations were concentrated at specific nucleotides within the binding motifs for certain transcription factors and predicted to significantly reduce the motif match score, thus potentially resulting in reduced transcription factor binding. In some cases, the reduction in motif match score for some transcription factors was accompanied by an increase in others, meaning that the mutations may create de novo transcription factor binding sites. In other cases, recurrent mutations were proximal to genes implicated in cancer and altered enhancer activity, suggesting that these mutations could lead to changes in oncogene or tumor suppressor expression. Although further characterization of these mutations is needed, particularly in the cell types in which the annotated regulatory elements are active, these results suggest that regulatory site mutations undergo positive selection in human tumors and thus may promote tumorigenesis.

Melton C, Reuter JA, Spacek DV, Snyder M. Recurrent somatic mutations in regulatory regions of human cancer genomes. Nat Genet 2015 Jun 8 [Epub ahead of print].