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A Significant Regulatory Mutation Burden at a High‐Affinity Position of the CTCF Motif in Gastrointestinal Cancers
Author(s) -
Umer Husen M.,
Cavalli Marco,
Dabrowski Michal J.,
Diamanti Klev,
Kruczyk Marcin,
Pan Gang,
Komorowski Jan,
Wadelius Claes
Publication year - 2016
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23014
Subject(s) - biology , ctcf , gene , transcription factor , genetics , regulatory sequence , cancer research , mutation , suppressor , somatic cell , computational biology , enhancer
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.