Integrated molecular analysis reveals hypermethylation and overexpression of HOX genes to be poor prognosticators in isocitrate dehydrogenase mutant glioma

• Verfasst von: Mamatjan, Yasin [VerfasserIn]
• Verfasst von: Voisin, Mathew R [VerfasserIn]
• Verfasst von: Nassiri, Farshad [VerfasserIn]
• Verfasst von: Moraes, Fabio Y [VerfasserIn]
• Verfasst von: Bunda, Severa [VerfasserIn]
• Verfasst von: So, Jonathan [VerfasserIn]
• Verfasst von: Salih, Mira [VerfasserIn]
• Verfasst von: Shirahata, Mitsuaki [VerfasserIn]
• Verfasst von: Ono, Takahiro [VerfasserIn]
• Verfasst von: Shimizu, Hiroaki [VerfasserIn]
• Verfasst von: Schrimpf, Daniel [VerfasserIn]
• Verfasst von: Deimling, Andreas von [VerfasserIn]
• Verfasst von: Aldape, Kenneth D [VerfasserIn]
• Verfasst von: Zadeh, Gelareh [VerfasserIn]
• Titel: Integrated molecular analysis reveals hypermethylation and overexpression of HOX genes to be poor prognosticators in isocitrate dehydrogenase mutant glioma
• Verf.angabe: Yasin Mamatjan, Mathew R Voisin, Farshad Nassiri, Fabio Y Moraes, Severa Bunda, Jonathan So, Mira Salih, Mitsuaki Shirahata, Takahiro Ono, Hiroaki Shimizu, Daniel Schrimpf, Andreas von Deimling, Kenneth D Aldape, and Gelareh Zadeh
• E-Jahr: 2023
• Jahr: 20 July 2023
• Umfang: 14 S.
• Fussnoten: Gesehen am 17.09.2024
• Titel Quelle: Enthalten in: Neuro-Oncology
• Ort Quelle: Oxford : Oxford Univ. Press, 1999
• Jahr Quelle: 2023
• Band/Heft Quelle: 25(2023), 11 vom: Nov., Seite 2028-204
• ISSN Quelle: 1523-5866
• DOI: doi:10.1093/neuonc/noad126
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1902701836

Abstract

Background.   Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Within isocitrate dehydrogenase (IDH)-mutant gliomas, there is a high variability in survival and a need to more accurately predict outcome. - Methods.   To identify and characterize a predictive signature of outcome in gliomas, we utilized an integrative molecular analysis (using methylation, mRNA, copy number variation (CNV), and mutation data), analyzing a total of 729 IDH-mutant samples including a test set of 99 from University Health Network (UHN) and 2 validation cohorts including the German Cancer Research Center (DKFZ) and The Cancer Genome Atlas (TCGA). - Results.   Cox regression analysis of methylation data from the UHN cohort identified CpG-based signatures that split the glioma cohort into 2 prognostic groups strongly predicting survival that were validated using 2 independent cohorts from TCGA and DKFZ (all P-values < .0001). The methylation signatures that predicted poor outcomes also exhibited high CNV instability and hypermethylation of HOX gene probes. Integrated multi-platform analyses using mRNA and methylation (iRM) showed that parallel HOX gene overexpression and simultaneous hypermethylation were significantly associated with increased mutational load, high aneuploidy, and worse survival (P-value < .0001). A 7-HOX gene signature was developed and validated using the most significantly associated HOX genes with patient outcome in both 1p/19q codeleted and non-codeleted IDHmut gliomas. - Conclusions.   HOX gene methylation and expression provide important prognostic information in IDH-mutant gliomas that are not captured by current molecular diagnostics. A 7-HOX gene signature of outcome shows significant survival differences in both 1p/19q codeleted and non-codeleted IDH-mutant gliomas.