Gene expression–based subtyping is widely accepted as a relevant source of disease stratification. Despite the technique’s widespread use, its translational and clinical utility is hampered by discrepant results, which are probably related to differences in data processing and algorithms applied to diverse patient cohorts, sample preparation methods and gene expression platforms. In the absence of a clear methodological ‘gold standard’ to perform such analyses, a more general framework that integrates and compares multiple strategies is needed to define common disease patterns in a principled, unbiased manner. Described here is such a framework and its application to elucidate the intrinsic subtypes of Colorectal cancer (CRC).
Analytical workflow of the Colorectal Cancer Subtyping Consortium
CRC is a frequently lethal disease with heterogeneous outcomes and drug responses. To resolve inconsistencies among the reported gene expression-based CRC classifications and facilitate clinical translation, a multinational team of scientists formed a consortium dedicated to large-scale data sharing and analytics across expert groups. They show marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMSs) with distinguishing features:
- CMS1 (microsatellite instability immune, 14%), hypermutated, microsatellite unstable and strong immune activation;
- CMS2 (canonical, 37%), epithelial, marked WNT and MYC signaling activation;
- CMS3 (metabolic, 13%), epithelial and evident metabolic dysregulation; and
- CMS4 (mesenchymal, 23%), prominent transforming growth factor-β activation, stromal invasion and angiogenesis.
Samples with mixed features (13%) possibly represent a transition phenotype or intratumoral heterogeneity. The researchers consider the CMS groups the most robust classification system currently available for CRC-with clear biological interpretability-and the basis for future clinical stratification and subtype-based targeted interventions.
Molecular associations of consensus molecular subtype groups