Urologic oncology · 2025
Promoter hypermethylation drives a paradoxical up regulation of hTERT with prognostic implications in bladder cancer.
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Anwar Iqra, Pandith Arshad A, Rasool Shayaq Ul Abeer, Manzoor Usma, Mir Khurshid I, Lone Iqbal M, Walvir Nazia M, Lone Tawseef A, Wani Mohammad S
Аннотация
INTRODUCTION: The human telomerase reverse transcriptase (hTERT) upregulation is a common feature in many cancers. While telomerase activity is often linked to gene expression, the relationship between promoter methylation and hTERT levels can be complex. This study aimed to investigate the association between hTERT promoter hypermethylation and its expression for prognosis and pathogenesis of bladder cancer.
METHODS: A total of 50 histologically confirmed bladder cancer tissue samples and matched adjacent normal controls were evaluated in a single-center prospective study. Promoter methylation was assessed by methylation-specific PCR (MS-PCR) targeting the CpG-rich hTERT promoter region, while protein expression was analyzed by immunohistochemistry using standardized scoring criteria. For validation, TCGA-BLCA data were analyzed for TERT mRNA expression, promoter methylation (TSS1500 and gene body regions), copy-number alterations (CNA), and survival outcomes. Correlation analyses and Kaplan-Meier plots were used for integrative assessment.
RESULTS: Promoter hypermethylation of hTERT was detected in 90% of bladder cancers, with 80% showing high hTERT protein expression. A strong positive association between promoter hypermethylation and high protein expression was observed (P = 0.04). This was corroborated by TCGA data showing a significant upregulation of TERT mRNA in bladder tumors. The expression of hTERT was at its strongest at stage IV, though this trend was not significant in the larger TCGA cohort (P = 0.256) The large-scale survival analysis revealed no significant association between TERT expression with OS (P = 0.76), PFS (0.95), DFS (P = 0.88) and pan-cancer analysis. TERT amplification was linked to markedly higher expression levels, but weak correlation between methylation and expression at selected CpG loci and methylation at TSS1500 or gene body regions and expression CONCLUSION: Our findings demonstrate that hTERT promoter hypermethylation is paradoxically associated with increased protein expression in bladder cancer, possibly through disruption of repressor binding within the THOR region. Although hTERT expression lacks prognostic value, its consistent upregulation suggests potential use as a screening biomarker and supports exploration of telomerase-targeted therapeutic strategies.
METHODS: A total of 50 histologically confirmed bladder cancer tissue samples and matched adjacent normal controls were evaluated in a single-center prospective study. Promoter methylation was assessed by methylation-specific PCR (MS-PCR) targeting the CpG-rich hTERT promoter region, while protein expression was analyzed by immunohistochemistry using standardized scoring criteria. For validation, TCGA-BLCA data were analyzed for TERT mRNA expression, promoter methylation (TSS1500 and gene body regions), copy-number alterations (CNA), and survival outcomes. Correlation analyses and Kaplan-Meier plots were used for integrative assessment.
RESULTS: Promoter hypermethylation of hTERT was detected in 90% of bladder cancers, with 80% showing high hTERT protein expression. A strong positive association between promoter hypermethylation and high protein expression was observed (P = 0.04). This was corroborated by TCGA data showing a significant upregulation of TERT mRNA in bladder tumors. The expression of hTERT was at its strongest at stage IV, though this trend was not significant in the larger TCGA cohort (P = 0.256) The large-scale survival analysis revealed no significant association between TERT expression with OS (P = 0.76), PFS (0.95), DFS (P = 0.88) and pan-cancer analysis. TERT amplification was linked to markedly higher expression levels, but weak correlation between methylation and expression at selected CpG loci and methylation at TSS1500 or gene body regions and expression CONCLUSION: Our findings demonstrate that hTERT promoter hypermethylation is paradoxically associated with increased protein expression in bladder cancer, possibly through disruption of repressor binding within the THOR region. Although hTERT expression lacks prognostic value, its consistent upregulation suggests potential use as a screening biomarker and supports exploration of telomerase-targeted therapeutic strategies.