CTCF/cohesin-binding Sites Are Frequently Mutated in Cancer

Overview

Journal Nat Genet

Specialty Genetics

Date 2015 Jun 9

PMID 26053496

Citations 241

Authors

Riku Katainen

Kashyap Dave

Esa Pitkanen

Kimmo Palin

Teemu Kivioja

Niko Valimaki

Alexandra E Gylfe

Heikki Ristolainen

Ulrika A Hanninen

Tatiana Cajuso

Johanna Kondelin

Tomas Tanskanen

Jukka-Pekka Mecklin

Heikki Jarvinen

Laura Renkonen-Sinisalo

Anna Lepisto

Eevi Kaasinen

Outi Kilpivaara

Sari Tuupanen

Martin Enge

Jussi Taipale

Lauri A Aaltonen

Affiliations

Soon will be listed here.

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.

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