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

Abstract

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.

Advances in Molecular Pathology, Diagnosis and Treatment of Spinal Cord Astrocytomas

“… 54 This type of tumor exhibits the loss of H3K27me3 and EZHIP proteins but is lacking histone mutations. 55 The prognosis of GBM_MID is similar to that of adult GBM (IDH wildtype). PDGFRA amplification and mutations of the mismatch repair genes and TP53 were the common molecular characteristics of GBM_MID.…”

“…PDGFRA amplification and mutations of the mismatch repair genes and TP53 were the common molecular characteristics of GBM_MID. 55 , 56 Chromosome 7p gain/amplification and 10q loss, EGFR amplification, and TERT promoter mutation, which serve as the diagnostic molecular criteria of adult GBM, were rarely seen in GBM_MID. 55 Although GBM_MID was originally discovered in the midline structure, it also widely occurs in other nonmidline structures.…”

“… 55 , 56 Chromosome 7p gain/amplification and 10q loss, EGFR amplification, and TERT promoter mutation, which serve as the diagnostic molecular criteria of adult GBM, were rarely seen in GBM_MID. 55 Although GBM_MID was originally discovered in the midline structure, it also widely occurs in other nonmidline structures. 55 – 57 These facts suggest that “GBM_MID” may not be a suitable term of this tumor type as GBM_MID describes a group of tumors with similar epigenetic features rather than clinical characteristics.…”

“… 55 Although GBM_MID was originally discovered in the midline structure, it also widely occurs in other nonmidline structures. 55 – 57 These facts suggest that “GBM_MID” may not be a suitable term of this tumor type as GBM_MID describes a group of tumors with similar epigenetic features rather than clinical characteristics. Currently, a systematic analysis of GBM_MID is lacking, and the conclusions about its molecular and clinical features are mainly based on several small sample studies.…”

Pediatric-type high-grade gliomas with PDGFRA amplification in adult patients with Li-Fraumeni syndrome: clinical and molecular characterization of three cases

“…A log2 ratio ± 0.35 was used as the cutoff for amplification/loss and a log2 ratio − 0.415 was used as the cut-off for homozygous loss. To identify significantly recurrent copy number amplifications and deletions at arm level and focal level, focal CNV was defined as affected regions spanning less than 50% of a chromosome arm [16].…”