CTCF/cohesin-binding sites are frequently mutated in cancer
Open accessAbstract
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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Mutations that alter the loop anchor sites of oncogene-containing insulated neighborhoods make an important contribution to the misregulation of gene expression that is inherent to the cancer state.
“These observations are consistent with the idea that mutations that alter the loop anchor sites of oncogene-containing insulated neighborhoods make an important contribution to the misregulation of gene expression that is inherent to the cancer state (Flavahan et al., 2016; Hnisz et al., 2016; Katainen et al., 2015).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Katainen et al., 2015
Somatic mutations occur frequently and recurrently in the loop anchors of oncogene-containing insulated neighborhoods in a variety of cancer cells.
“Somatic mutations occur frequently and recurrently in the loop anchors of oncogene-containing Insulated neighborhoods in a variety of cancer cells (Figure 2E).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Katainen et al., 2015
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- Authors
- Katainen, R., Dave, K., Pitkänen, E., Palin, K., Kivioja, T., Välimäki, N., Gylfe, A. E., Ristolainen, H., Hänninen, U. A., Cajuso, T., Kondelin, J., Tanskanen, T., Mecklin, J.-P., Järvinen, H., Renkonen-Sinisalo, L., Lepistö, A., Kaasinen, E., Kilpivaara, O., Tuupanen, S., Enge, M., Taipale, J., & Aaltonen, L. A.
- Affiliations
- University of Helsinki (FI)
- Karolinska Institutet (SE)
- University of Eastern Finland (FI)
- Helsinki University Hospital (FI)
- Corresponding author
- Taipale, Jussi
- Aaltonen, Lauri A
- ORCID
- Venue
- Nature Genetics
- Published
- 2015-06-08
- Volume
- 47
- Issue
- 7
- Pages
- 818-821
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1565385417
- Cited by
- 447
- References
- 29
- Citations by year
- 2026: 22 · 2025: 21 · 2024: 28 · 2023: 37 · 2022: 33 · 2021: 50 · 2020: 44 · 2019: 54 · 2018: 43 · 2017: 51 · 2016: 55 · 2015: 9
- FWCI
- 41.73
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- CTCF, cohesin, DNA mutations, colorectal cancer, mutational signatures, enhancers, non-coding genome, mutational hotspots, chromatin regulation
- MeSH terms
- CCCTC-Binding Factor, Cohesins, Binding Sites, Chromosomal Proteins, Non-Histone, Humans, Regulatory Sequences, Nucleic Acid, Repressor Proteins, Colorectal Neoplasms, Consensus Sequence, Point Mutation, Cell Cycle Proteins, Genetic Predisposition to Disease, Genetic Association Studies
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