Ó³»­´«Ã½

BACKGROUND: Telomerase reactivation, a hallmark of many cancers, is associated with expression of its catalytic subunit, hTERT. However, the prognostic significance of telomere maintenance mechanisms in pediatric medulloblastoma remains poorly defined.METHODS: In this multi-institutional retrospective study of telomerase expression and regulation in newly diagnosed children with medulloblastoma, and expression were assessed by qRT-PCR, normalized to non-neoplastic brain control samples. promoter methylation was analyzed using quantitative pyrosequencing and Illumina 450k methylation array. Cox proportional-hazard regression analyses evaluated the association of expression with progression-free survival (PFS) or overall survival (OS). Spearman correlation and Kruskal-Wallis tests correlated promoter methylation and expression and assessed variations among medulloblastoma subgroups, respectively.RESULTS: Among 74 patients with available expression and outcome data, higher expression was associated with worse OS (HR=1.22, 95% CI: 1.01-1.47, p=0.036) and PFS (HR=1.17, 95% CI: 1.00-1.37, p=0.051) after adjusting for subgroup. Similar results were obtained when adjusting for metastatic status. Group 3 patients had the highest expression (p=0.001). Pyrosequencing data were available for 61 patients and 450k methylation array data for 292 patients. promoter was differentially methylated across subgroups with WNT followed by group 3 demonstrating the highest methylation on 450k (p<0.0001), findings that were confirmed by pyrosequencing. promoter methylation positively correlated with expression (Spearman correlation=0.42, p=0.02 by 450k and 0.34, p=0.007 by pyrosequencing). No significant correlation was observed between and expression.CONCLUSION: Elevated expression is associated with worse PFS and OS in medulloblastoma across subgroups, supporting telomerase inhibition as a potential therapeutic strategy.