title: A Significant Regulatory Mutation Burden at a High-Affinity Position of the CTCF Motif in Gastrointestinal Cancers.
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.
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, SE-751-24, Sweden.
authors.forename: Husen M
authors.initials: HM
authors.lastname: Umer
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SE-751 08, Sweden.
authors.forename: Marco
authors.initials: M
authors.lastname: Cavalli
authors.affiliation: Institute of Computer Science, Polish Academy of Sciences, Warsaw, 01-248, Poland.
authors.forename: Michal J
authors.initials: MJ
authors.lastname: Dabrowski
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, SE-751-24, Sweden.
authors.forename: Klev
authors.initials: K
authors.lastname: Diamanti
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, SE-751-24, Sweden.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kruczyk
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SE-751 08, Sweden.
authors.forename: Gang
authors.initials: G
authors.lastname: Pan
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, SE-751-24, Sweden.|Institute of Computer Science, Polish Academy of Sciences, Warsaw, 01-248, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Komorowski
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SE-751 08, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Wadelius
mesh_terms: D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D030541:Databases, Genetic; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D009154:Mutation; D011485:Protein Binding; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D014157:Transcription Factors
keywords: CTCF; WGS; driver mutations; motifs; mutated binding sites; noncoding regulatory regions; whole-genome sequencing