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, 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 database was utilized to download RNA-seq data from 638 CRC and 51 control samples. Differential expressed genes were screened and intersected with 2086 TMRGs, resulting in the identification of 976 TMRGs. 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. 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 functional significance of PDE1B in CRC cell lines was investigated through MTT assays, cell colony formation assays, transwell assays and flow cytometry. RESULTS: A total of 976 DE-TMRGs were enriched in telomere/DNA replication pathways. A three-gene signature (PDE1B, TFAP2B, and HSPA1A) stratified patients into high- and low-risk groups with divergent survival (AUC >0.60, validated externally). High-risk patients had advanced N/M stages, elevated M0/M2 macrophages, reduced CD4+ memory T cells, and upregulated immune checkpoints. Nomogram integrating risk score, age, and N/M stage accurately predicted 1-/3-/5-year survival. Low-risk patients showed greater 5-fluorouracil sensitivity. PDE1B expression was significantly reduced in CRC tissues and correlated with advanced stages. Functional assays confirmed PDE1B overexpression suppressed proliferation, migration, invasion, and induced apoptosis in CRC cells. CONCLUSION: This study identifies a moderately predictive telomere maintenance-related gene signature as an independent prognostic predictor in CRC. The risk stratification model effectively discriminates patients with distinct survival patterns, tumor microenvironments, and therapeutic responses, while the integrated nomogram offers additional reference information for survival analysis, albeit with only moderate predictive accuracy. These findings indicate telomere maintenance-related gene signature could serve as a preliminary auxiliary risk stratification tool for postoperative CRC patients, PDE1B may also serve as a potential epithelial tumor-suppressor target for future preclinical studies.