Recurrent somatic mutations in regulatory regions of human cancer genomes

Nat Genet. 2015 Jul;47(7):710-6. doi: 10.1038/ng.3332. Epub 2015 Jun 8.


Aberrant regulation of gene expression in cancer can promote survival and proliferation of cancer cells. Here we integrate whole-genome sequencing data from The Cancer Genome Atlas (TCGA) for 436 patients from 8 cancer subtypes with ENCODE and other regulatory annotations to identify point mutations in regulatory regions. We find evidence for positive selection of mutations in transcription factor binding sites, consistent with these sites regulating important cancer cell functions. Using a new method that adjusts for sample- and genomic locus-specific mutation rates, we identify recurrently mutated sites across individuals with cancer. Mutated regulatory sites include known sites in the TERT promoter and many new sites, including a subset in proximity to cancer-related genes. In reporter assays, two new sites display decreased enhancer activity upon mutation. These data demonstrate that many regulatory regions contain mutations under selective pressure and suggest a greater role for regulatory mutations in cancer than previously appreciated.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Binding Sites
  • Conserved Sequence
  • Gene Expression Regulation, Neoplastic
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genome, Human
  • Humans
  • Molecular Sequence Annotation
  • Mutation
  • Neoplasms / genetics*
  • Promoter Regions, Genetic*