In Silico Analysis of the Dual Role of Tumor Microenvironment on Colon Cancer Subtypes

Background: Colon cancer is a highly heterogeneous disease, marked by substantial intra- and inter-tumor variability. Investigating transcriptomic profiles can offer deeper insight into this heterogeneity. However, most genome-transcriptome studies on colon cancer have primarily focused on examining primary tumors and matched normal tissues, often neglecting the multi-stage disease progression. Objective: To establish unique molecular colon subtypes based on the progression in transcriptomic profiles. Additionally, to investigate the implicated factors, such as mutations and the tumor microenvironment (TME), that affect colon cancer progression and their implications for therapy. Methods: RNA-sequencing data from The Cancer Genome Atlas Colon Cancer (TCGA-COAD) cohort were obtained from the UCSC Xena database, including 47 early and 39 late-stage tumor samples. Heterogeneity was exposed by tracking cancer progression through the multi-stages of cancer development. Hierarchical clustering revealed colon subtypes with varying progression, and differentially expressed genes (DEGs) were identified between these subtypes. The DEGs were subjected to Recursive Feature Elimination and mutational analyses to reveal driver genes. The TME and biological pathways were analyzed. The study was validated with an independent GEO dataset. Results: Two novel colon subtypes were identified. Significant enrichment pathways and varied mutations in cancer driver genes were found in both subtypes. Interestingly, concurrent downregulation of oncogenes and tumor suppressor genes was observed in one of the subtypes, suggesting a link to the dual functionality of CD4 and CD8 T-cells in the TME. Conclusion: Overall, our study demonstrates a complex relationship between TME and gene expression of driver genes. The presence of immune cell fractions with dual functions suggests a balanced early-to-late-stage progression. The findings provide insights into the disease progression that potentially contribute to the development of targeted therapies.