Colorectal cancer, Consensus molecular subtype, Clinical outcome, Tumor epithelium, Tumor microenvironment, Gene expression signature, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

Abstract Background Accumulating evidence has suggested that cancer progression and therapeutic response depend on both tumor epithelium (EPI) and tumor microenvironment (TME). However, the dependency of clinical outcomes on the tumor EPI vs. the TME has neither been clearly defined nor quantified. Methods We classified 2373 colorectal cancer (CRC) tumors into the consensus molecular subtypes (CMS1-4) and generated the 10-gene TMES and the 10-gene EPIS signatures as the serendipitous derivatives of the most (positively vs. negatively) correlated genes of a highly-prognostic, ~ 500-gene signature we previously identified. Distinct TME vs. EPI cellular features of the signature genes were identified by CIBERSORT deconvolution and validated by scRNASEQ in an independent public dataset. Results The TMES signature was strongly associated with the immune/stromal TME-rich CMS1/CMS4 subtypes that portended worse survival, whereas the EPIS signature was predominantly related to the TME-poor, epithelial CMS2/CMS3 classes that portended better survival. Multivariable Cox regression analysis against 29 TME-related signatures revealed that the TMES signature was the most strikingly impacted by the “Cancer-associated fibroblasts” signature (HR: 10.87 vs. 0.13, both P