The genomic landscape of 2,023 colorectal cancers

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  • dc.contributor.author Cornish, Alex J.
  • dc.contributor.author Arnedo Pac, Claudia
  • dc.contributor.author López Bigas, Núria
  • dc.contributor.author Houlston, Richard S.
  • dc.date.accessioned 2025-04-07T06:15:05Z
  • dc.date.available 2025-04-07T06:15:05Z
  • dc.date.issued 2024
  • dc.description.abstract Colorectal carcinoma (CRC) is a common cause of mortality1, but a comprehensive description of its genomic landscape is lacking2-9. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia colipks+ colibactin in rectal cancers10 and the importance of the SBS93 signature11-13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.
  • dc.description.sponsorship R.S.H., I.P.M.T. and N.L.-B. are supported by the Wellcome Trust (214388), T.A.G. and A.S are supported by the Wellcome Trust (202778/B/16/Z). I.P.M.T. is supported by Cancer Research UK (C6199/A27327). R.S.H. is supported by Cancer Research UK (C1298/A8362). D.C.W. is supported by the NIHR Manchester Biomedical Research Centre (NIHR203308). A. Sottoriva is supported by Cancer Research UK (A22909). T.A.G. is supported by Cancer Research UK (A19771 and DRCNPG-May21\100001). P.Q. and H.M.W. are supported by Cancer Research UK Grand Challenge Initiative (OPTIMISTICC C10674/A27140). P.Q. is also supported by Yorkshire Cancer Research L386 and is a National Institute of Health Senior Investigator. B.N was funded through the Cancer Research UK Birmingham Centre award (C17422/A25154). C.A.-P. was supported by “la Caixa” Foundation (ID 100010434) fellowship (LCF/BQ/ES18/11670011). L.B.A was supported by grants from the US National Institutes of Health, including NIEHS R01ES032547 and NCI R01CA269919. G.C. is supported by the Italian Association for Cancer Research (AIRC) under MFAG 2020-ID 24913. We acknowledge funding from the National Institute of Health (NCI U54 CA217376) to A.S and T.A.G. This work was also supported by a Wellcome Trust award to the Centre for Evolution and Cancer at the ICR (105104/Z/14/Z). D.N.C. is supported a by Cancer Research UK Advanced Clinician Scientist Fellowship award (C26642/A27963). D.N.C., D.C.W. and A.F. acknowledge support from the Oxford NIHR Comprehensive Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. N.L.-B. acknowledges funding from the European Research Council (consolidator grant 682398) and ERDF/Spanish Ministry of Science, Innovation and Universities–Spanish State Research Agency/DamReMap Project (RTI2018-094095-B-I00) and Asociación Española Contra el Cáncer (AECC) (GC16173697BIGA). IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from the Spanish Ministry of Economy and Competitiveness (MINECO; Government of Spain) and is supported by CERCA (Generalitat de Catalunya). This research was made possible through access to data in the National Genomic Research Library, which is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The National Genomic Research Library holds data provided by patients and collected by the NHS as part of their care and data collected as part of their participation in research. The National Genomic Research Library is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. We are grateful to all participants and other individuals involved in the study.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Cornish AJ, Gruber AJ, Kinnersley B, Chubb D, Frangou A, Caravagna G, et al. The genomic landscape of 2,023 colorectal cancers. Nature. 2024 Sep;633(8028):127-36. DOI: 10.1038/s41586-024-07747-9
  • dc.identifier.doi http://dx.doi.org/10.1038/s41586-024-07747-9
  • dc.identifier.issn 0028-0836
  • dc.identifier.uri http://hdl.handle.net/10230/70096
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nature. 2024 Sep;633(8028):127-36
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/682398
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-094095-B-I00
  • dc.rights © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Cancer genomics
  • dc.subject.keyword Colorectal cancer
  • dc.subject.keyword Evolutionary genetics
  • dc.subject.keyword Genetics research
  • dc.subject.keyword Next-generation sequencing
  • dc.title The genomic landscape of 2,023 colorectal cancers
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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