Molecular landscape of IDH‐wild‐type, H3‐wild‐type glioblastomas of adolescents and young adults

• Published in: Neuropathology and applied neurobiology Vol. 48; no. 4; pp. e12802 - n/a
• Main Authors: Shi, Zhi‐Feng, Li, Kay Ka‐Wai, Huang, Queenie Jun‐Qi, Wang, Wei‐Wei, Kwan, Johnny Sheung‐Him, Chen, Hong, Liu, Xiang‐Zhi, Li, Wen‐Cai, Chan, Danny Tat‐Ming, Zhang, Zhen‐Yu, Mao, Ying, Ng, Ho‐Keung
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-06-2022
• Subjects: Adolescent; Adolescents; anaplastic PXA; Astrocytes; Astrocytoma - pathology; Brain Neoplasms - pathology; Brain tumors; Central nervous system diseases; DNA Methylation; DNA Modification Methylases - genetics; DNA Repair Enzymes - genetics; GBM_midline; Glioblastoma; Glioblastoma - pathology; glioblastoma RTK/mesenchymal; glioblastomas in adolescents and young adults; Humans; Isocitrate dehydrogenase; Isocitrate Dehydrogenase - genetics; Mesenchyme; methylation class; Mismatch repair; Mutation; Proto-Oncogene Proteins B-raf - genetics; Survival; Tumors; Young Adult; Young adults; glioblastoma RTK/mesenchymal; methylation class; anaplastic PXA; GBM_midline; glioblastomas in adolescents and young adults
• ISSN: 0305-1846; 1365-2990
• DOI: 10.1111/nan.12802

Objective
We aimed to characterise glioblastomas of adolescents and young adults (AYAs) that were isocitrate dehydrogenase (IDH) wild type (wt) and H3wt.
Materials and Methods
Fifty such patients (aged 16–32) were studied by methylation profiling, targeted sequencing and targeted RNA‐seq.
Results
Tumours predominantly clustered into three methylation classes according to the terminology of Capper et al. (2018): (anaplastic) pleomorphic xanthoastrocytoma (PXA) (21 cases), GBM_midline (15 cases) and glioblastoma RTK/mesenchymal (seven cases). Two cases clustered with ANA_PA, four cases with LGG classes and one with GBM_MYCN. Only fifteen cases reached a calibrated score >0.84 when the cases were uploaded to DKFZ Classifier. GBM_midline‐clustered tumours had a poorer overall survival (OS) compared with the PXA‐clustered tumours (p = 0.030). LGG‐clustered cases had a significantly better survival than GBM_midline‐clustered tumours and glioblastoma RTK/mesenchymal‐clustered tumours. Only 13/21 (62%) of PXA‐clustered cases were BRAF V600E mutated. Most GBM_midline‐clustered cases were not located in the midline. GBM_midline‐clustered cases were characterised by PDGFRA amplification/mutation (73.3%), mutations of mismatch repair genes (40.0%), and all showed H3K27me3 and EZH1P loss, and an unmethylated MGMT promoter. Across the whole cohort, MGMT promoter methylation and wt TERT promoter were favourable prognosticators. Mismatch repair gene mutations were poor prognosticators and together with methylation class and MGMT methylation, maintained their significance in multivariate analyses. BRAF mutation was a good prognosticator in the PXA‐clustered tumours.
Conclusion
Methylation profiling is a useful tool in the diagnosis and prognostication of AYA glioblastomas, and the methylation classes have distinct molecular characteristics. The usual molecular diagnostic criteria for adult IDHwt glioblastoma should be applied with caution within the AYA age group.
We studied a cohort of IDH‐wildtype, H3‐wildtype glioblastomas of adolescents and young adults (AYA) with genome‐wide DNA methylation profiling, targeted sequencing and TERT promoter sequencing. We found that AYA glioblastomas can be separated into clinically significant groups by methylation profiling and these groups have distinct molecular features. TERT promoter mutation, EGFR amplification and combined whole chromosome +7/−10 are not common in this cohort. And, MGMT methylation, TERTp mutation and MMR mutation are prognostic significance.