Recurrent and functional regulatory mutations in breast cancer

Nature. 2017 Jul 6;547(7661):55-60. doi: 10.1038/nature22992. Epub 2017 Jun 28.


Genomic analysis of tumours has led to the identification of hundreds of cancer genes on the basis of the presence of mutations in protein-coding regions. By contrast, much less is known about cancer-causing mutations in non-coding regions. Here we perform deep sequencing in 360 primary breast cancers and develop computational methods to identify significantly mutated promoters. Clear signals are found in the promoters of three genes. FOXA1, a known driver of hormone-receptor positive breast cancer, harbours a mutational hotspot in its promoter leading to overexpression through increased E2F binding. RMRP and NEAT1, two non-coding RNA genes, carry mutations that affect protein binding to their promoters and alter expression levels. Our study shows that promoter regions harbour recurrent mutations in cancer with functional consequences and that the mutations occur at similar frequencies as in coding regions. Power analyses indicate that more such regions remain to be discovered through deep sequencing of adequately sized cohorts of patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics*
  • Cohort Studies
  • E2F Transcription Factors / metabolism
  • Exome / genetics
  • Gene Expression Regulation, Neoplastic / genetics*
  • Hepatocyte Nuclear Factor 3-alpha / genetics
  • Hepatocyte Nuclear Factor 3-alpha / metabolism
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Mutation*
  • Promoter Regions, Genetic / genetics*
  • Protein Binding / genetics
  • RNA, Long Noncoding / genetics
  • Receptors, Estrogen / antagonists & inhibitors


  • E2F Transcription Factors
  • FOXA1 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • NEAT1 long non-coding RNA, human
  • RMRP non-coding RNA, human
  • RNA, Long Noncoding
  • Receptors, Estrogen