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

Authors
  • Umer, Husen M1
  • Cavalli, Marco2
  • Dabrowski, Michal J3
  • Diamanti, Klev1
  • Kruczyk, Marcin1
  • Pan, Gang2
  • Komorowski, Jan1, 3
  • Wadelius, Claes2
  • 1 Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, SE-751-24, Sweden. , (Sweden)
  • 2 Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SE-751 08, Sweden. , (Sweden)
  • 3 Institute of Computer Science, Polish Academy of Sciences, Warsaw, 01-248, Poland. , (Poland)
Type
Published Article
Journal
Human Mutation
Publisher
Wiley (John Wiley & Sons)
Publication Date
Sep 01, 2016
Volume
37
Issue
9
Pages
904–913
Identifiers
DOI: 10.1002/humu.23014
PMID: 27174533
Source
Medline
Keywords
License
Unknown

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.

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