Longer Telomeres Raise Pan-Cancer Risk via TERT-Driven Genomic and Immune Disruption

Telomeres protect chromosome ends from degradation and fusion, but their length has a complex, bidirectional relationship with cancer. While critically short telomeres can suppress tumor growth by triggering senescence, excessively long telomeres may confer unlimited replicative capacity to malignant cells. This study set out to rigorously quantify the causal contribution of telomere length to cancer risk across multiple tumor types and identify the molecular intermediaries responsible.

The researchers applied two-sample Mendelian randomization (MR) using GWAS data from 472,174 European individuals (MRCIEU, telomere length exposure) and 500,244 individuals from the FinnGen R11 pan-cancer dataset (outcome). Multiple MR methods — inverse-variance weighted (IVW), MR-Egger, and weighted mode — were used with strict instrumental variable quality control (P < 5×10⁻⁶, F-statistic >10, LD pruning r² < 0.001). Leave-one-out and funnel plot analyses confirmed robustness. Longer telomere length was causally associated with increased risk across all 33 tested cancer endpoints (IVW OR = 1.27–1.41, all P < 0.001), spanning head and neck, respiratory, digestive, skin, breast, urological, neurological, and hematological malignancies.

From the 121 telomere-length-associated SNPs, SNPense annotation identified 143 protein-coding genes. Protein-protein interaction (PPI) network analysis using STRING, followed by MCODE and cytoHubba algorithms, pinpointed TERT (telomerase reverse transcriptase) as the most central hub gene with the highest MCC score (169). Functional enrichment via GO and KEGG highlighted pathways in telomere maintenance, CST complex function, and genome integrity. Reactome and Human Phenotype analyses further connected these genes to hematological phenotypes and telomere length regulation.

TCGA pan-cancer RNA-seq analysis confirmed TERT is overexpressed in 16 cancer types including cholangiocarcinoma (CHOL), hepatocellular carcinoma (LIHC), and lung adenocarcinoma (LUAD). This finding was independently validated through RT-qPCR in 16 paired tumor versus normal human cell lines representing diverse tissue origins. ROC curve analysis demonstrated strong diagnostic utility for TERT, with AUC exceeding 0.85 in 16 cancer types and reaching 0.97 in lung squamous cell carcinoma (LUSC). Immune infiltration analysis revealed TERT expression positively correlates with Th2 cells (r = 0.42) — associated with immunosuppression — and negatively with dendritic cells (r = −0.38) and macrophages (r = −0.31), suggesting TERT actively remodels the tumor immune microenvironment to evade immune surveillance.

Taken together, this study proposes a mechanistic framework whereby genetically longer telomeres promote pan-cancer susceptibility through two converging pathways: TERT-mediated genomic instability enabling continued malignant proliferation, and immune microenvironment remodeling that suppresses anti-tumor immunity. These findings position TERT as a high-priority diagnostic biomarker and therapeutic target across multiple cancer types.