DNA-methylome-assisted classification of patients with poor prognostic subventricular zone associated IDH-wildtype glioblastoma

• Published in: Acta neuropathologica Vol. 144; no. 1; pp. 129 - 142
• Main Authors: Adeberg, Sebastian, Knoll, Maximilian, Koelsche, Christian, Bernhardt, Denise, Schrimpf, Daniel, Sahm, Felix, König, Laila, Harrabi, Semi Ben, Hörner-Rieber, Juliane, Verma, Vivek, Bewerunge-Hudler, Melanie, Unterberg, Andreas, Sturm, Dominik, Jungk, Christine, Herold-Mende, Christel, Wick, Wolfgang, von Deimling, Andreas, Debus, Juergen, Rieken, Stefan, Abdollahi, Amir
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.07.2022; Springer; Springer Nature B.V
• Subjects: Brain cancer; Chemoradiotherapy; Chemotherapy; Chromosome 10; Chromosome 19; Classification; Copy number; CpG islands; Discordance; DNA; DNA methylation; Gene mutations; Glioblastoma; Glioblastoma multiforme; Magnetic resonance imaging; Medicine; Medicine & Public Health; Methylation; Molecular modelling; Neurosciences; Next-generation sequencing; Original Paper; Pathology; Phenotypes; Prognosis; Radiation therapy; Stem cells; Subventricular zone; Transcriptomes; Transplantation; Tumors
• ISSN: 0001-6322; 1432-0533; 1432-0533
• DOI: 10.1007/s00401-022-02443-2

Glioblastoma (GBM) derived from the “stem cell” rich subventricular zone (SVZ) may constitute a therapy-refractory subgroup of tumors associated with poor prognosis. Risk stratification for these cases is necessary but is curtailed by error prone imaging-based evaluation. Therefore, we aimed to establish a robust DNA methylome-based classification of SVZ GBM and subsequently decipher underlying molecular characteristics. MRI assessment of SVZ association was performed in a retrospective training set of IDH-wildtype GBM patients ( n  = 54) uniformly treated with postoperative chemoradiotherapy. DNA isolated from FFPE samples was subject to methylome and copy number variation (CNV) analysis using Illumina Platform and cnAnalysis450k package. Deep next-generation sequencing (NGS) of a panel of 130 GBM-related genes was conducted (Agilent SureSelect/Illumina). Methylome, transcriptome, CNV, MRI, and mutational profiles of SVZ GBM were further evaluated in a confirmatory cohort of 132 patients (TCGA/TCIA). A 15 CpG SVZ methylation signature (SVZM) was discovered based on clustering and random forest analysis. One third of CpG in the SVZM were associated with MAB21L2 / LRBA . There was a 14.8% ( n  = 8) discordance between SVZM vs. MRI classification. Re-analysis of these patients favored SVZM classification with a hazard ratio (HR) for OS of 2.48 [95% CI 1.35–4.58], p  = 0.004 vs. 1.83 [1.0–3.35], p  = 0.049 for MRI classification. In the validation cohort, consensus MRI based assignment was achieved in 62% of patients with an intraclass correlation (ICC) of 0.51 and non-significant HR for OS (2.03 [0.81–5.09], p  = 0.133). In contrast, SVZM identified two prognostically distinct subgroups (HR 3.08 [1.24–7.66], p  = 0.016). CNV alterations revealed loss of chromosome 10 in SVZM– and gains on chromosome 19 in SVZM– tumors. SVZM– tumors were also enriched for differentially mutated genes ( p  < 0.001). In summary, SVZM classification provides a novel means for stratifying GBM patients with poor prognosis and deciphering molecular mechanisms governing aggressive tumor phenotypes.