The genomic landscape of 2,023 colorectal cancers

• 成果类型: Article
• 署名作者: Cornish, Alex J.; Gruber, Andreas J.; Kinnersley, Ben; Chubb, Daniel; Frangou, Anna; Caravagna, Giulio; Noyvert, Boris; Lakatos, Eszter; Wood, Henry M.; Thorn, Steve; Culliford, Richard; Arnedo-Pac, Claudia; Househam, Jacob; Cross, William; Sud, Amit; Law, Philip; Ni Leathlobhair, Maire; Hawari, Aliah; Woolley, Connor; Sherwood, Kitty; Feeley, Nathalie; Guel, Gueler; Fernandez-Tajes, Juan; Zapata, Luis; Alexandrov, Ludmil B.; Murugaesu, Nirupa; Sosinsky, Alona; Mitchell, Jonathan; Lopez-Bigas, Nuria; Quirke, Philip; Church, David N.; Tomlinson, Ian P. M.; Sottoriva, Andrea; Graham, Trevor A.; Wedge, David C.; Houlston, Richard S.
• 署名单位: University of London; Institute of Cancer Research - UK; Royal Marsden NHS Foundation Trust; University of Konstanz; University of Manchester; University of London; University College London; University of Oxford; Max Planck Society; University of Trieste; Royal Marsden NHS Foundation Trust; University of London; Institute of Cancer Research - UK; University of Birmingham; Cancer Research UK; University of Birmingham; Chalmers University of Technology; University of Leeds; University of Oxford; Barcelona Institute of Science & Technology; Institute for Research in Biomedicine - IRB Barcelona; CIBER - Centro de Investigacion Biomedica en Red; CIBERONC; ICREA; University of London; University College London; Trinity College Dublin; University of Edinburgh; University of California System; University of California San Diego; University of California System; University of California San Diego; University of California System; University of California San Diego; University of London; Queen Mary University London; University of Oxford; Wellcome Centre for Human Genetics; Oxford University Hospitals NHS Foundation Trust; Human Technopole
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5329
• DOI: 10.1038/s41586-024-07747-9
• 发表日期: 2024-09-05
• 页码: 127-+
• 关键词: copy-number; mutational signatures; somatic mutations; fragile sites; DISCOVERY; selection; driver; expression; inference; prognosis

摘要

Colorectal carcinoma (CRC) is a common cause of mortality(1), but a comprehensive description of its genomic landscape is lacking(2-9). 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 coli(pks+) colibactin in rectal cancers(10) and the importance of the SBS93 signature(11-13), which suggests that diet or smoking is a risk factor. Immune-escape driver mutations(14) 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.