The genomic landscape of 2,023 colorectal cancers

Alex J. Cornish, Andreas J. Gruber, Ben Kinnersley, Daniel Chubb, Anna Frangou, Giulio Caravagna, Boris Noyvert, Eszter Lakatos, Henry M. Wood, Steve Thorn, Richard Culliford, Claudia Arnedo-Pac, Jacob Househam, William Cross, Amit Sud, Philip Law, Maire Ni Leathlobhair, Aliah Hawari, Connor Woolley, Kitty Sherwood, Nathalie Feeley, Güler Gül, Juan Fernandez-Tajes, Luis Zapata, Ludmil B. Alexandrov, Nirupa Murugaesu, Alona Sosinsky, Jonathan Mitchell, Nuria Lopez-Bigas, Philip Quirke, David N. Church, Ian P. M. Tomlinson (), Andrea Sottoriva, Trevor A. Graham, David C. Wedge and Richard S. Houlston
Additional contact information
Alex J. Cornish: Institute of Cancer Research
Andreas J. Gruber: University of Konstanz
Ben Kinnersley: Institute of Cancer Research
Daniel Chubb: Institute of Cancer Research
Anna Frangou: University of Oxford
Giulio Caravagna: University of Trieste
Boris Noyvert: University of Birmingham
Eszter Lakatos: Institute of Cancer Research
Henry M. Wood: University of Leeds
Steve Thorn: University of Oxford
Richard Culliford: Institute of Cancer Research
Claudia Arnedo-Pac: The Barcelona Institute of Science and Technology
Jacob Househam: Institute of Cancer Research
William Cross: Institute of Cancer Research
Amit Sud: Institute of Cancer Research
Philip Law: Institute of Cancer Research
Maire Ni Leathlobhair: Trinity College
Aliah Hawari: University of Manchester
Connor Woolley: University of Oxford
Kitty Sherwood: University of Oxford
Nathalie Feeley: University of Oxford
Güler Gül: University of Edinburgh
Juan Fernandez-Tajes: University of Oxford
Luis Zapata: Institute of Cancer Research
Ludmil B. Alexandrov: UC San Diego
Nirupa Murugaesu: Queen Mary University of London
Alona Sosinsky: Queen Mary University of London
Jonathan Mitchell: Queen Mary University of London
Nuria Lopez-Bigas: The Barcelona Institute of Science and Technology
Philip Quirke: University of Leeds
David N. Church: University of Oxford
Ian P. M. Tomlinson: University of Oxford
Andrea Sottoriva: Institute of Cancer Research
Trevor A. Graham: Institute of Cancer Research
David C. Wedge: University of Manchester
Richard S. Houlston: Institute of Cancer Research

Nature, 2024, vol. 633, issue 8028, 127-136

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07747-9

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