A Significant Regulatory Mutation Burden at a High-Affinity Position of the CTCF Motif in Gastrointestinal Cancers
2016 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 37, no 9, 904-913 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2016. Vol. 37, no 9, 904-913 p.
mutated binding sites, motifs, noncoding regulatory regions, CTCF, driver mutations, whole-genome sequencing, WGS
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-305547DOI: 10.1002/humu.23014ISI: 000382777100009PubMedID: 27174533OAI: oai:DiVA.org:uu-305547DiVA: diva2:1038948
FunderSwedish Cancer Society, 15 0878Swedish Research CouncileSSENCE - An eScience Collaboration, DEC 2015/16/W/NZ2/00314