The C250T Mutation of TERTp Might Grant a Better Prognosis to Glioblastoma by Exerting Less Biological Effect on Telomeres and Chromosomes Than the C228T Mutation.

Simple Summary: In our glioblastoma patients treated with standard therapy, the TERTp C250T mutation occurred less frequently than the C228T mutation. Patients with the C250T mutation had better prognosis than those with either TERTp-wt or TERTp C228T mutations, even when adjusted for key glioblastoma prognostic factors. This may be due to the lesser involvement of the C250T mutation in telomere- and chromosome-related pathways, as evidenced by the results of a gene enrichment analysis adjusted for MGMTp methylation status: TERTp C250T was differentially enriched compared to TERTp-wt and C228T. There were no differences according to TERTp mutation status in the mutations or copy number variants of other genes commonly present in glioblastoma. The biological pathways by which TERTp and MGMTp exert their effects are independent. The aim of this study was to determine how TERTp mutations impact glioblastoma prognosis. Materials and Methods: TERTp mutations were assessed in a retrospective cohort of 258 uniformly treated glioblastoma patients. RNA-sequencing and whole exome sequencing results were available in a subset of patients. Results: Overall, there were no differences in outcomes between patients with mutated TERTp-wt or TERTp. However, we found significant differences according to the type of TERTp mutation. Progression-free survival (mPFS) was 9.1 months for those with the C250T mutation and 7 months for those with either the C228T mutation or TERTp-wt (p = 0.016). Overall survival (mOS) was 21.9 and 15 months, respectively (p = 0.026). This differential effect was more pronounced in patients with MGMTp methylation (mPFS: p = 0.008; mOS: p = 0.021). Multivariate analysis identified the C250T mutation as an independent prognostic factor for longer mOS (HR 0.69; p = 0.044). We found no differences according to TERTp mutation status in molecular alterations common in glioblastoma, nor in copy number variants in genes related to alternative lengthening of telomeres. Nevertheless, in the gene enrichment analysis adjusted for MGMTp methylation status, some Reactome gene sets were differentially enriched, suggesting that the C250T mutation may exert a lesser effect on telomeres or chromosomes. Conclusions: In our series, patients exhibiting the C250T mutation had a more favorable prognosis compared to those with either TERPp-wt or TERTp C228T mutations. Additionally, our findings suggest a reduced involvement of the C250T mutation in the underlying biological mechanisms related to telomeres. [ABSTRACT FROM AUTHOR]