How Can We Improve Subtyping of Colon Adenocarcinoma for Precision Oncology? Multi-Omics Consensus Clustering Reveals Immunologically Active and Therapeutically Distinct Molecular Groups

Colon adenocarcinoma (COAD) is a heterogeneous malignancy whose molecular complexity limits effective therapy. Existing transcriptome-based classifications capture only part of this diversity. To refine COAD stratification, we integrated genomic, epigenomic, and transcriptomic data from 297 The Cancer Genome Atlas patients. Ten complementary clustering algorithms were combined through a consensus ensemble framework to ensure robust and unbiased subtype discovery. The resulting molecular subtypes were characterized by genomic alterations, signaling pathways, tumor microenvironment features, and predicted therapeutic responses. As a result, four reproducible molecular subtypes (CS1-CS4) were identified. CS1 displayed enrichment of extracellular matrix organization and epithelial-mesenchymal transition signatures, suggesting invasive potential. CS2 exhibited transcriptional similarity to PD-1 responders, indicating potential benefit from immune checkpoint blockade. CS3 represented a mutation-driven subtype with frequent <i>APC</i>, <i>TP53</i>, and <i>KRAS</i> alterations and extensive copy number gains. CS4 showed the highest immune infiltration, elevated tumor mutational burden, and enhanced sensitivity to 5-fluorouracil and cetuximab. Validation across four independent cohorts confirmed the reproducibility of these subtypes. This integrative multi-omics framework refines the molecular taxonomy of COAD, revealing immunologically active and therapeutically distinct subgroups. The classification not only bridges genomic, epigenomic, and transcriptomic regulation but also provides a practical roadmap for precision oncology by linking molecular features to potential treatment strategies.