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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| Hauptverfasser: | , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
20 July 2023
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| In: |
Neuro-Oncology
Year: 2023, Jahrgang: 25, Heft: 11, Pages: 2028-204 |
| ISSN: | 1523-5866 |
| DOI: | 10.1093/neuonc/noad126 |
| Online-Zugang: | 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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| Verfasserangaben: | 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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| 245 | 1 | 0 | |a Integrated molecular analysis reveals hypermethylation and overexpression of HOX genes to be poor prognosticators in isocitrate dehydrogenase mutant glioma |c 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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| 520 | |a 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. | ||
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| 700 | 1 | |a Moraes, Fabio Y |e VerfasserIn |4 aut | |
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