SSCS: A Stage Supervised Subtyping System for Colorectal Cancer.

Colorectal cancer (CRC) is heterogeneous and deadly, and the exact cause of the disease is unknown. Recent progress indicated that CRC is not a single disease, but a group of diseases with significant heterogeneity. Three previous CRC subtyping systems: microsatellite instability (MSI), consensus molecular subtypes (CMS), and tumor-node-metastases (TNM) stage were evaluated for their molecular and clinical implications. Results suggested that the MSI and CMS systems are prognostic and predictive mostly in early-stage CRC. As the stage remains an influential factor for CRC subtype analysis, we developed a new subtyping system named stage supervised CRC subtypes (SSCS), in order to better stratify CRC biologically and clinically. Our subtyping system can be used to classify CRC patients into five subtypes (SSCS1-5). SSCS1 was found to have the highest frequency of MSI-H cases compared to the remaining four subtypes. SSCS2 had the most favorable prognosis, whereas the worst prognosis was seen in SSCS4. SSCS3 had cell cycle and metabolism-related gene sets upregulation, and SSCS5 subtype was enriched with amplicon-associated gene sets. Moreover, tumor-infiltrating fibroblast was found to be predictive for poor disease-free survival (DFS) only within the SSCS4 subtype. Conventional dendritic cells (cDC), on the contrary, were associated with favorable DFS in the SSCS3 subtype. Our study provides a new subtyping system SSCS, which can be used for better stratify CRC patients compared to current standards. Further exploration of the subtype-specific cell types has the potential to be novel therapies for CRC.