A Significant Regulatory Mutation Burden at a High-Affinity Position of the CTCF Motif in Gastrointestinal Cancers

Hum Mutat. 2016 Sep;37(9):904-13. doi: 10.1002/humu.23014. Epub 2016 Jun 2.

Abstract

Somatic mutations drive cancer and there are established ways to study those in coding sequences. It has been shown that some regulatory mutations are over-represented in cancer. We develop a new strategy to find putative regulatory mutations based on experimentally established motifs for transcription factors (TFs). In total, we find 1,552 candidate regulatory mutations predicted to significantly reduce binding affinity of many TFs in hepatocellular carcinoma and affecting binding of CTCF also in esophagus, gastric, and pancreatic cancers. Near mutated motifs, there is a significant enrichment of (1) genes mutated in cancer, (2) tumor-suppressor genes, (3) genes in KEGG cancer pathways, and (4) sets of genes previously associated to cancer. Experimental and functional validations support the findings. The strategy can be applied to identify regulatory mutations in any cell type with established TF motifs and will aid identifications of genes contributing to cancer.

Keywords: CTCF; WGS; driver mutations; motifs; mutated binding sites; noncoding regulatory regions; whole-genome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Carcinoma, Hepatocellular / genetics*
  • Databases, Genetic
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Genetic Predisposition to Disease
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / genetics*
  • Mutation*
  • Protein Binding
  • Sequence Analysis, DNA
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • Transcription Factors