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

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 an...

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Main Authors: Mamatjan, Yasin (Author) , Voisin, Mathew R (Author) , Nassiri, Farshad (Author) , Moraes, Fabio Y (Author) , Bunda, Severa (Author) , So, Jonathan (Author) , Salih, Mira (Author) , Shirahata, Mitsuaki (Author) , Ono, Takahiro (Author) , Shimizu, Hiroaki (Author) , Schrimpf, Daniel (Author) , Deimling, Andreas von (Author) , Aldape, Kenneth D (Author) , Zadeh, Gelareh (Author)
Format: Article (Journal)
Language:English
Published: 20 July 2023
In: Neuro-Oncology
Year: 2023, Volume: 25, Issue: 11, Pages: 2028-204
ISSN:1523-5866
DOI:10.1093/neuonc/noad126
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1093/neuonc/noad126
Verlag, lizenzpflichtig, Volltext: https://academic.oup.com/neuro-oncology/article/25/11/2028/7227261
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Author Notes: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
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Summary: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.
Item Description:Gesehen am 17.09.2024
Physical Description:Online Resource
ISSN:1523-5866
DOI:10.1093/neuonc/noad126

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