Population-based cohort study of prognostic genome and transcriptome signatures in colorectal cancers

Colorectal cancer (CRC) is caused by a sequence of somatic genomic alterations affecting driver genes in core cancer pathways. A population-based cohort study with long-term follow-up investigated the whole genomes and transcriptomes of 1,063 primary CRCs. From the 96 mutated driver genes, 9 were not previously implicated in CRC, 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 CRC-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 tumors divided into two classes with different levels of hypoxia and infiltration of immune and stromal cells. The authors conclude that this study constitutes the largest integrated genome and transcriptome analysis of CRC, and interlinks mutations, gene expression, and patient outcomes.