Molecular subtyping and prognostic model construction based on endosome-related genes in colorectal cancer

The endosome plays a crucial role in tumor cell material transport, signal regulation, and tumor immune microenvironment modeling, but the molecular characteristics, subtyping significance, and prognostic value of endosome-related genes (ERGs) in colorectal cancer (CRC) have not been systematically elucidated. This study aims to analyze the molecular heterogeneity of CRC from the perspective of ERGs and evaluate ERGs' clinical and therapeutic significance.

The transcriptome and clinical data of CRC from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were integrated, identifying 63 CRC-related ERGs. Molecular typing of CRC samples was conducted based on consensus clustering analysis, and comparison of differences in survival outcomes, tumor immune microenvironment characteristics, and potential response to immunotherapy was performed among different subtypes. An ERG prognostic risk model was constructed through differential expression analysis and was validated in an independent cohort. Combining functional experiments and drug sensitivity analysis, the potential mechanisms and therapeutic value of key genes were investigated.

The CRC samples were divided into two significantly different subtypes of endosome-related molecules (cluster 1 and cluster 2). Compared with cluster 2, cluster 1 patients had better overall survival rates, more active immune cell infiltration (such as B cell and mast cell enrichment), and lower Tumor Immune Dysfunction and Exclusion (TIDE) scores, suggesting that they may be more likely to benefit from immune checkpoint inhibitor therapy. The prognostic model constructed based on 8-ERGs showed good predictive performance in both the training and validation sets. Further analysis revealed that the key prognostic gene MAGEA1 was significantly upregulated in CRC tissues and closely associated with poor pathological staging and shorter overall survival time. Mechanism analysis suggested that MAGEA1 may promote CRC cell proliferation by regulating the CDK4/6-Rb signaling axis, and the CDK4/6 inhibitor ribociclib (LEE011) exhibited stronger anti-proliferative effects on MAGEA1 overexpressing cells. In addition, the constructed integrated risk score and clinical parameter nomogram can be used for personalized survival prediction.

This study systematically revealed the molecular heterogeneity of CRC from the perspective of ERGs, identified clinically significant prognostic subtypes, and key gene MAGEA1. The constructed ERG prognostic model and nomogram provide new theoretical basis and potential targets for risk stratification and personalized treatment of CRC patients.