Prognostic genome and transcriptome signatures in colorectal cancers

• 成果类型: Article
• 署名作者: Nunes, Luis; Li, Fuqiang; Wu, Meizhen; Luo, Tian; Hammarstrom, Klara; Torell, Emma; Ljuslinder, Ingrid; Mezheyeuski, Artur; Edqvist, Per-Henrik; Lofgren-Burstroem, Anna; Zingmark, Carl; Edin, Sofia; Larsson, Chatarina; Mathot, Lucy; Osterman, Erik; Osterlund, Emerik; Ljungstroem, Viktor; Neves, Ines; Yacoub, Nicole; Gudnadottir, Unnur; Birgisson, Helgi; Enblad, Malin; Ponten, Fredrik; Palmqvist, Richard; Xu, Xun; Uhlen, Mathias; Wu, Kui; Glimelius, Bengt; Lin, Cong; Sjoblom, Tobias
• 署名单位: Uppsala University; Chinese Academy of Sciences; Hangzhou Institute of Medicine, CAS; Beijing Genomics Institute (BGI); Beijing Genomics Institute (BGI); Umea University; Umea University; Uppsala University; Uppsala University Hospital; Karolinska Institutet; Royal Institute of Technology; University of Oslo
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3912
• DOI: 10.1038/s41586-024-07769-3
• 发表日期: 2024-09-05
• 页码: 137-+
• 关键词: r-spondin fusions; mutational signatures; carcinoma; pathways; reveals; Heterogeneity; progression; expression; landscape; selection

摘要

Colorectal cancer is caused by a sequence of somatic genomic alterations affecting driver genes in core cancer pathways(1). 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 TGF beta 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.