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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, p. 904-913Article 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, p. 904-913
Keywords [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, id: diva2:1038948
Funder
Swedish Cancer Society, 15 0878Swedish Research CouncileSSENCE - An eScience Collaboration, DEC 2015/16/W/NZ2/00314Available from: 2016-10-20 Created: 2016-10-19 Last updated: 2018-01-25Bibliographically approved
In thesis
1. Computational Modelling of Gene Regulation in Cancer: Coding the noncoding genome
Open this publication in new window or tab >>Computational Modelling of Gene Regulation in Cancer: Coding the noncoding genome
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Technological advancements have enabled quantification of processes within and around us. The information stored within our body converts into petabytes of data. Processing and learning from such data requires comprehensive computational programs and software systems. We developed software programs to systematically investigate the process of gene regulation in the human genome. Gene regulation is a complex process where several genomic elements control expression of a gene through recruiting many transcription factor (TF) proteins. The TFs recognize specific DNA sequences known as motifs. DNA mutations in regulatory elements and particularly in TF motifs may cause gene deregulation. Therefore, defining the landscape of regulatory elements and their roles in cancer and complex diseases is of major importance.

We developed an algorithm (tfNet) to identify regulatory elements based on transcription factor binding sites. tfNet identified nearly 144,000 regulatory elements in five human cell lines. Investigating the elements we identified TF interaction networks and enrichment of many GWAS SNPs. We also defined the regulatory landscape for other conditions and species. Next, we investigated the role of regulatory elements in cancer. Cancer is initiated and developed by genetic aberrations in the genome. Genetic changes that are present in a cancer genome are obtained through whole genome sequencing technologies. We analyzed somatic mutations that had been detected in 326 whole genomes of liver cancer patients. Our results indicated 907 candidate mutations affecting TF motifs. Genome wide alignment of the mutated motifs revealed a significant enrichment of mutations in a highly conserved position of the CTCF motif. Gene expression analysis exhibited disruption of topologically associated domains in the mutated samples. We also confirmed the mutational pattern in pancreatic, gastric and esophagus cancers. Finally, enrichment of cancer associated gene sets and pathways suggested great role of noncoding mutations in cancer.

To systematically analyze DNA mutations in TF motifs, we developed an online database system (funMotifs). Publicly available datasets were collected for thousands experiments. The datasets were integrated using a logistic regression model. Functionality annotations and scores for motifs of 519 TFs were derived. The database allows for identification of variants affecting functional motifs in a selected tissue type. Finally, a comprehensive analysis was performed to identify mutations overlapping functional TF motifs in 37 cancer types. Somatic mutations from a pan-cancer cohort of 2,515 cancer whole genomes were investigated. A significant enrichment of mutations in the CpG site of the CEBPB motif was identified. Overall, 10,806 mutated regulatory elements were identified including 406 highly recurrent ones. Genes associated to the mutated elements were highly enriched for cancer-related pathways. Our analyses provide further insights onto the role of regulatory elements and their impacts on cancer development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 54
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1627
Keywords
Regulatory elements, gene regulation, cancer, motif, integrative database, software solutions for cancer data
National Category
Bioinformatics (Computational Biology)
Research subject
Bioinformatics
Identifiers
urn:nbn:se:uu:diva-339937 (URN)978-91-513-0220-1 (ISBN)
Public defence
2018-03-14, A1:111a, BMC, Husargatan 3, 09:00 (English)
Opponent
Supervisors
Available from: 2018-02-21 Created: 2018-01-24 Last updated: 2018-03-07

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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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