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A Significant Regulatory Mutation Burden at a High-Affinity Position of the CTCF Motif in Gastrointestinal Cancers
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
Polish Acad Sci, Inst Comp Sci, PL-01248 Warsaw, Poland..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2016 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 37, no 9, 904-913 p.Article in journal (Refereed) Published
Abstract [en]

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.
Keyword [en]
mutated binding sites, motifs, noncoding regulatory regions, CTCF, driver mutations, whole-genome sequencing, WGS
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-305547DOI: 10.1002/humu.23014ISI: 000382777100009PubMedID: 27174533OAI: oai:DiVA.org:uu-305547DiVA: diva2:1038948
Funder
Swedish Cancer Society, 15 0878Swedish Research CouncileSSENCE - An eScience Collaboration, DEC 2015/16/W/NZ2/00314
Available from: 2016-10-20 Created: 2016-10-19 Last updated: 2016-10-20Bibliographically approved

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Umer, Husen M.Cavalli, MarcoDiamanti, KlevPan, GangKomorowski, JanWadelius, Claes
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Computational Biology and BioinformaticsScience for Life Laboratory, SciLifeLabMedicinsk genetik och genomikDepartment of Cell and Molecular Biology
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