A global transcriptional network connecting noncoding mutations to changes in tumor gene expression

Nat Genet. 2018 Apr;50(4):613-620. doi: 10.1038/s41588-018-0091-2. Epub 2018 Apr 2.

Abstract

Although cancer genomes are replete with noncoding mutations, the effects of these mutations remain poorly characterized. Here we perform an integrative analysis of 930 tumor whole genomes and matched transcriptomes, identifying a network of 193 noncoding loci in which mutations disrupt target gene expression. These 'somatic eQTLs' (expression quantitative trait loci) are frequently mutated in specific cancer tissues, and the majority can be validated in an independent cohort of 3,382 tumors. Among these, we find that the effects of noncoding mutations on DAAM1, MTG2 and HYI transcription are recapitulated in multiple cancer cell lines and that increasing DAAM1 expression leads to invasive cell migration. Collectively, the noncoding loci converge on a set of core pathways, permitting a classification of tumors into pathway-based subtypes. The somatic eQTL network is disrupted in 88% of tumors, suggesting widespread impact of noncoding mutations in cancer.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Aldose-Ketose Isomerases / genetics
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Genes, Neoplasm*
  • Humans
  • Monomeric GTP-Binding Proteins / genetics
  • Mutation*
  • Neoplasm Invasiveness / genetics
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Quantitative Trait Loci
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • RNA, Untranslated / genetics
  • RNA, Untranslated / metabolism
  • Whole Genome Sequencing

Substances

  • Adaptor Proteins, Signal Transducing
  • DAAM1 protein, human
  • RNA, Messenger
  • RNA, Neoplasm
  • RNA, Untranslated
  • MTG2 protein, human
  • Monomeric GTP-Binding Proteins
  • Aldose-Ketose Isomerases