Prognostic genome and transcriptome signatures in colorectal cancers

Luís Nunes, Fuqiang Li, Meizhen Wu, Tian Luo, Klara Hammarström, Emma Torell, Ingrid Ljuslinder, Artur Mezheyeuski, Per-Henrik Edqvist, Anna Löfgren-Burström, Carl Zingmark, Sofia Edin, Chatarina Larsson, Lucy Mathot, Erik Osterman, Emerik Osterlund, Viktor Ljungström, Inês Neves, Nicole Yacoub, Unnur Guðnadóttir, Helgi Birgisson, Malin Enblad, Fredrik Ponten, Richard Palmqvist, Xun Xu, Mathias Uhlén, Kui Wu (), Bengt Glimelius (), Cong Lin () and Tobias Sjöblom ()
Additional contact information
Luís Nunes: Uppsala University
Fuqiang Li: BGI Research
Meizhen Wu: BGI Research
Tian Luo: BGI Research
Klara Hammarström: Uppsala University
Emma Torell: Uppsala University
Ingrid Ljuslinder: Umeå University
Artur Mezheyeuski: Uppsala University
Per-Henrik Edqvist: Uppsala University
Anna Löfgren-Burström: Umeå University
Carl Zingmark: Umeå University
Sofia Edin: Umeå University
Chatarina Larsson: Uppsala University
Lucy Mathot: Uppsala University
Erik Osterman: Uppsala University
Emerik Osterlund: Uppsala University
Viktor Ljungström: Uppsala University
Inês Neves: Uppsala University
Nicole Yacoub: Uppsala University
Unnur Guðnadóttir: Uppsala University
Helgi Birgisson: Akademiska sjukhuset
Malin Enblad: Akademiska sjukhuset
Fredrik Ponten: Uppsala University
Richard Palmqvist: Umeå University
Xun Xu: BGI Research
Mathias Uhlén: Karolinska Institutet
Kui Wu: BGI Research
Bengt Glimelius: Uppsala University
Cong Lin: BGI Research
Tobias Sjöblom: Uppsala University

Nature, 2024, vol. 633, issue 8028, 137-146

Abstract: Abstract Colorectal cancer is caused by a sequence of somatic genomic alterations affecting driver genes in core cancer pathways1. Here, to understand the functional and prognostic impact of cancer-causing somatic mutations, we analysed the whole genomes and transcriptomes of 1,063 primary colorectal cancers in a population-based cohort with long-term follow-up. From the 96 mutated driver genes, 9 were not previously implicated in colorectal cancer and 24 had not been linked to any cancer. Two distinct patterns of pathway co-mutations were observed, timing analyses identified nine early and three late driver gene mutations, and several signatures of colorectal-cancer-specific mutational processes were identified. Mutations in WNT, EGFR and TGFβ pathway genes, the mitochondrial CYB gene and 3 regulatory elements along with 21 copy-number variations and the COSMIC SBS44 signature correlated with survival. Gene expression classification yielded five prognostic subtypes with distinct molecular features, in part explained by underlying genomic alterations. Microsatellite-instable tumours divided into two classes with different levels of hypoxia and infiltration of immune and stromal cells. To our knowledge, this study constitutes the largest integrated genome and transcriptome analysis of colorectal cancer, and interlinks mutations, gene expression and patient outcomes. The identification of prognostic mutations and expression subtypes can guide future efforts to individualize colorectal cancer therapy.

Date: 2024
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DOI: 10.1038/s41586-024-07769-3

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