c2b1600b04c245191c2b88d246a86cb0 pmc_10886885.pdf 50a98385356ed7904e16a0b84eb3f2c360e937ba pmc_10886885.pdf 3ef39acd2a208f619bd879f1b203896fffc35f311f7328de2ae3b591c323b6c8 pmc_10886885.pdf Title: 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 Subject: 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. Keywords: TERTp mutations; glioblastoma; MGMTp methylation; RNA-Seq differential expression analysis; whole-exome sequencing Author: Teresa Gorria, Carme Crous, Estela Pineda, Ainhoa Hernandez, Marta Domenech, Carolina Sanz, Pedro Jares, Ana María Muñoz-Mármol, Oriol Arpí-Llucía, Bárbara Melendez, Marta Gut, Anna Esteve, Anna Esteve-Codina, Genis Parra, Francesc Alameda, Cristina Carrato, Iban Aldecoa, Mar Mallo, Nuria de la Iglesia and Carmen Balana Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Sat Feb 17 08:00:57 2024 CET ModDate: Sat Feb 17 10:16:00 2024 CET Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 14 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2036529 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- SSNIUI+VnURWPalladioL-Bold Type 1 Custom yes yes yes 10 0 SAWCSS+URWPalladioL-Bold Type 1 Custom yes yes yes 16 0 KTLCWE+URWPalladioL-Roma Type 1 Custom yes yes yes 22 0 UYQBVO+URWPalladioL-Ital Type 1 Custom yes yes yes 27 0 BMKHPZ+URWPalladioL-BoldItal Type 1 Custom yes yes yes 32 0 BFTPJC+VnURWPalladioL Type 1 Custom yes yes yes 37 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 54 0 YZIJXT+CMSY10 Type 1 Builtin yes yes yes 71 0 YSCNED+EURM10 Type 1 Builtin yes yes yes 76 0 KANHHF+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 103 0 KANHKF+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 109 0 KANJGL+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 115 0 KANJHM+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 121 0 KANJHN+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 124 0 KANJHO+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 127 0 KANKDM+PalatinoLinotype-Roman TrueType MacRoman yes yes no 130 0 KANHHF+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 143 0 KANHKF+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 149 0 KANJGL+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 155 0 KANJHM+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 161 0 KANJHN+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 164 0 KANJHO+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 167 0 KANKDM+PalatinoLinotype-Roman TrueType MacRoman yes yes no 170 0 KANHHF+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 189 0 KANHKF+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 195 0 KANJGL+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 201 0 KANJHM+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 207 0 KANJHN+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 210 0 KANJHO+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 213 0 KANKDM+PalatinoLinotype-Roman TrueType MacRoman yes yes no 216 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-06-21 02:48:01 CEST RepresentationInformation: pmc_10886885.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-06-20 02:37:13 CEST Size: 2036529 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 445 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Material and Methods Destination: section.2 Children: Item: Title: Patients Destination: subsection.2.1 Item: Title: Molecular Analyses Destination: subsection.2.2 Item: Title: Statistical Analyses Destination: subsection.2.3 Item: Title: Ethics Statement Destination: subsection.2.4 Item: Title: Results Destination: section.3 Children: Item: Title: Patients Destination: subsection.3.1 Item: Title: TERTp Mutations Destination: subsection.3.2 Item: Title: Outcomes Destination: subsection.3.3 Item: Title: Discussion Destination: section.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: appendix.A. Info: Title: 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 Author: Teresa Gorria, Carme Crous, Estela Pineda, Ainhoa Hernandez, Marta Domenech, Carolina Sanz, Pedro Jares, Ana María Muñoz-Mármol, Oriol Arpí-Llucía, Bárbara Melendez, Marta Gut, Anna Esteve, Anna Esteve-Codina, Genis Parra, Francesc Alameda, Cristina Carrato, Iban Aldecoa, Mar Mallo, Nuria de la Iglesia and Carmen Balana Subject: 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. 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