Crucial Role of Telomere Maintenance-Related Genes in Survival Prediction and Subtype Identification in Colorectal Cancer

Background: Telomere maintenance-related genes (TMRGs) are implicated in Colorectal cancer (CRC) development and progression, but their prognostic value and clinical relevance remain insufficiently explored. This study aims to develop a TMRG-based prognostic model and elucidate its clinical utility in CRC management. Methods: The Cancer Genome Atlas (TCGA) database was utilized to download RNA-seq data from 638 CRC and 51 control samples. Differential expressed genes (DEGs) were screened and intersected with 2086 TMRGs, resulting in the identification of 976 TMRGs exhibiting survival differences. Through univariate and multivariate Cox regression analysis, a prognostic model comprising three telomere maintenance-related biomarkers (PDE1B, TFAP2B, and HSPA1A) was developed and validated using an external dataset (GSE28722). Functional enrichment analysis was performed to further elucidate the roles of these 976 TMRGs in CRC. Subsequently, by integrating the model risk score with clinical features, a nomogram was constructed to predict the survival outcomes of CRC patients. Additionally, an in-depth investigation of the immuno-infiltration, functional variation and drug sensitivity analysis were performed in two risk subgroups defined by the prognostic model. Finally, the expression and functional significance of PDE1B in CRC cell lines was investigated through MTT assays, colony formation assays, transwell assays and flow cytometry. Results: Among 21,930 DEGs, 976 DE-TMRGs were enriched in telomere maintenance and DNA replication. The prognostic model stratified patients into high- and low-risk groups with distinct survival outcomes. High-risk patients exhibited advanced pathological stages, increased immune infiltration (M0/M2 macrophages), and reduced CD4+T cells. The nomogram integrating risk scores, age, and pathologic N/M stage accurately predicted 1-, 3-, and 5-year survival. Low-risk patients showed higher sensitivity to 5-fluorouracil. PDE1B expression was significantly reduced in CRC tissues and correlated with advanced stages. Overexpression of PDE1B suppressed CRC cell proliferation, metastasis and induced apoptosis. Conclusion: This study establishes a robust TMRG-based prognostic model for CRC, integrating molecular insights with clinical parameters. PDE1B emerges as a potential biomarker and therapeutic target, with low expression linked to poor prognosis. The model’s predictive accuracy, combined with immune profiling and drug sensitivity data, offers a framework for personalized treatment strategies, enhancing prognostic assessment and therapeutic decision-making in CRC.