The genomic landscape of 2,023 colorectal cancers
Journal article, 2024
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 Escherichiacolipks+ 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.
Author
Alex J. Cornish
Institute of Cancer Research
Andreas J. Gruber
Faculty of Biology, Medicine and Health
University of Konstanz
Ben Kinnersley
University College London (UCL)
Institute of Cancer Research
Daniel Chubb
Institute of Cancer Research
Anna Frangou
Max Planck Society
University of Oxford
Giulio Caravagna
Institute of Cancer Research
University of Trieste
Boris Noyvert
University of Birmingham
Eszter Lakatos
Institute of Cancer Research
Chalmers, Mathematical Sciences, Applied Mathematics and Statistics
Henry M. Wood
University of Leeds
Steve Thorn
University of Oxford
Richard Culliford
Institute of Cancer Research
Claudia Arnedo-Pac
Centro de Investigación Biomédica en Red de Cáncer
Catalan Institution for Research and Advanced Studies
IRB Barcelona - Institute for Research in Biomedicine
Jacob Househam
Institute of Cancer Research
William Cross
Institute of Cancer Research
University College London (UCL)
Amit Sud
Institute of Cancer Research
Philip Law
Institute of Cancer Research
Maire Ni Leathlobhair
Trinity College Dublin
Aliah Hawari
Faculty of Biology, Medicine and Health
Connor Woolley
University of Oxford
Kitty Sherwood
University of Edinburgh
University of Oxford
Nathalie Feeley
University of Edinburgh
University of Oxford
Güler Gül
University of Edinburgh
Juan Fernandez-Tajes
University of Oxford
Luis Zapata
Institute of Cancer Research
Ludmil B. Alexandrov
University of California
University of California at San Diego (UCSD)
Moores Cancer Center
Nirupa Murugaesu
Barts Cancer Institute
Alona Sosinsky
Barts Cancer Institute
Jonathan Mitchell
Barts Cancer Institute
Nuria Lopez-Bigas
Catalan Institution for Research and Advanced Studies
IRB Barcelona - Institute for Research in Biomedicine
Centro de Investigación Biomédica en Red de Cáncer
Philip Quirke
University of Leeds
David N. Church
Wellcome Trust Centre for Human Genetics
NIHR Oxford Biomedical Research Centre
Ian P.M. Tomlinson
University of Oxford
Andrea Sottoriva
Institute of Cancer Research
Fondazione Human Technopole
Trevor A. Graham
Institute of Cancer Research
David C. Wedge
Faculty of Biology, Medicine and Health
Richard S. Houlston
Institute of Cancer Research
Nature
0028-0836 (ISSN) 1476-4687 (eISSN)
Vol. 633 8028 127-136Areas of Advance
Health Engineering
Subject Categories (SSIF 2011)
Medical Genetics
Cancer and Oncology
DOI
10.1038/s41586-024-07747-9