title: CTCF/cohesin-binding sites are frequently mutated in cancer.
abstract: Cohesin is present in almost all active enhancer regions, where it is associated with transcription factors. Cohesin frequently colocalizes with CTCF (CCCTC-binding factor), affecting genomic stability, expression and epigenetic homeostasis. Cohesin subunits are mutated in cancer, but CTCF/cohesin-binding sites (CBSs) in DNA have not been examined for mutations. Here we report frequent mutations at CBSs in cancers displaying a mutational signature where mutations in A•T base pairs predominate. Integration of whole-genome sequencing data from 213 colorectal cancer (CRC) samples and chromatin immunoprecipitation sequencing (ChIP-exo) data identified frequent point mutations at CBSs. In contrast, CRCs showing an ultramutator phenotype caused by defects in the exonuclease domain of DNA polymerase ɛ (POLE) displayed significantly fewer mutations at and adjacent to CBSs. Analysis of public data showed that multiple cancer types accumulate CBS mutations. CBSs are a major mutational hotspot in the noncoding cancer genome.
authors.affiliation: 1] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. [2] Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Riku
authors.initials: R
authors.lastname: Katainen
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kashyap
authors.initials: K
authors.lastname: Dave
authors.affiliation: 1] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. [2] Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Esa
authors.initials: E
authors.lastname: Pitkänen
authors.affiliation: 1] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. [2] Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Kimmo
authors.identifier: 0000000246216128
authors.initials: K
authors.lastname: Palin
authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Kivioja
authors.affiliation: 1] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. [2] Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Niko
authors.initials: N
authors.lastname: Välimäki
authors.affiliation: 1] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. [2] Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Gylfe
authors.affiliation: 1] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. [2] Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Ristolainen
authors.affiliation: 1] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. [2] Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Ulrika A
authors.initials: UA
authors.lastname: Hänninen
authors.affiliation: 1] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. [2] Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Cajuso
authors.affiliation: 1] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. [2] Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Kondelin
authors.affiliation: 1] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. [2] Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Tomas
authors.initials: T
authors.lastname: Tanskanen
authors.affiliation: Department of Surgery, Jyväskylä Central Hospital, University of Eastern Finland, Jyväskylä, Finland.
authors.forename: Jukka-Pekka
authors.initials: JP
authors.lastname: Mecklin
authors.affiliation: Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Järvinen
authors.affiliation: 1] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. [2] Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Helsinki, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Renkonen-Sinisalo
authors.affiliation: Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Lepistö
authors.affiliation: 1] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. [2] Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Eevi
authors.initials: E
authors.lastname: Kaasinen
authors.affiliation: 1] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. [2] Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Kilpivaara
authors.affiliation: 1] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. [2] Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Sari
authors.initials: S
authors.lastname: Tuupanen
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Enge
authors.affiliation: 1] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. [2] Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jussi
authors.initials: J
authors.lastname: Taipale
authors.affiliation: 1] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. [2] Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D001665:Binding Sites; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone / Q000502:physiology*; D015179:Colorectal Neoplasms; D016384:Consensus Sequence; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D017354:Point Mutation; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000502:physiology*; D000097722:Cohesins
chemical_list: D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D012097:Repressor Proteins; D000097722:Cohesins; C000619697:CTCF protein, human