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Genetic classification of colorectal cancer subtypes

▸ Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med 2015;21:1350–6.

Cancers display heterogeneity, and thus personalised cancer therapy has the potential to improve patient outcome. Guinney and colleagues developed a consortium with independent analysis of large-scale transcriptome data using independent groups to generate a network of gene pathways that can be ascribed to specific, hitherto unknown colorectal cancer (CRC) subtypes. Whole-genome gene-expression data were used from 18 CRC datasets and a cohort size of 4151 patients. Cancer phenotype was taken into account, and the data were normalised to ensure a comparable form. Statistical analysis generated network plots with each patient representing a node. Each cluster of nodes was investigated for common genomic aberrations and epigenetic and phenotypic features. Each cluster was termed a consensus molecular subtype (CMS). Four CMS were discovered. Approximately 20% of patients’ data did not cluster into any subtype. CMS1 showed a gene expression consistent with strong Th1 immune response and a genetic profile consistent with microsatellite instability; BRAF mutations, a mutator phenotype and a high methylation phenotype. CMS2 (the most frequent subtype) demonstrated a canonical subtype with high WNT signalling and MYC activation along with genes associated with the cell cycle. CMS3 gene expression displayed metabolism deregulation and a high incidence of KRAS mutations. CMS4 showed a more stroma-cell-related gene expression, suggesting association with epithelial–mesenchymal transition, along with high angiogenic gene expression. CMS1 appeared more frequently in females with right-sided CRC and advanced disease, reflected by poor survival. CMS2 were mainly left sided. CMS4 cancers appeared to present with the most advanced disease and displayed the worst survival of all subtypes. It would have been interesting to see the clinical information of the non-consensus patients. This article displays the power of collaborative research, and using independent …

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