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

Adaptor Proteins, Signal Transducing / genetics Brain Neoplasms / diagnostic imaging DNA Copy Number Variations Epigenome Eye Proteins / genetics Glioblastoma / diagnostic imaging Humans Intracellular Signaling Peptides and Proteins / genetics Lateral Ventricles / diagnostic imaging Prognosis Retrospective Studies

Journal

Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041

Informations de publication

Date de publication:
07 2022
Historique:
received: 03 01 2022
accepted: 21 05 2022
revised: 04 05 2022
pubmed: 7 6 2022
medline: 25 6 2022
entrez: 6 6 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1007/s00401-022-02443-2 PMID: 35660939 PMC: PMC9217840
pubmed: 35660939
doi: 10.1007/s00401-022-02443-2
pii: 10.1007/s00401-022-02443-2
pmc: PMC9217840
doi:

Substances chimiques

Adaptor Proteins, Signal Transducing 0
Eye Proteins 0
Intracellular Signaling Peptides and Proteins 0
MAB21L2 protein, human 0
LRBA protein, human EC 2.7.10.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

129-142

Informations de copyright

© 2022. The Author(s).

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Auteurs

Sebastian Adeberg (S)

German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany. Sebastian.adeberg@med.uni-heidelberg.de.
National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany. Sebastian.adeberg@med.uni-heidelberg.de.
Department of Radiation Oncology, Heidelberg University Hospital (UKHD), Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. Sebastian.adeberg@med.uni-heidelberg.de.
Heidelberg Institute for Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), UKHD and DKFZ, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. Sebastian.adeberg@med.uni-heidelberg.de.
Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. Sebastian.adeberg@med.uni-heidelberg.de.
ORCID: 0000-0001-8463-514X

Maximilian Knoll (M)

German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Radiation Oncology, Heidelberg University Hospital (UKHD), Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Heidelberg Institute for Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), UKHD and DKFZ, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.

Christian Koelsche (C)

Department of Neuropathology, University Hospital of Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

Denise Bernhardt (D)

German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
Department of Radiation Oncology, TUM, Ismaninger Str. 22, 81675, Munich, Germany.

Daniel Schrimpf (D)

Department of Neuropathology, University Hospital of Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

Felix Sahm (F)

Department of Neuropathology, University Hospital of Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

Laila König (L)

German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Radiation Oncology, Heidelberg University Hospital (UKHD), Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Heidelberg Institute for Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), UKHD and DKFZ, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

Semi Ben Harrabi (SB)

German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Radiation Oncology, Heidelberg University Hospital (UKHD), Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Heidelberg Institute for Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), UKHD and DKFZ, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

Juliane Hörner-Rieber (J)

German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Radiation Oncology, Heidelberg University Hospital (UKHD), Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Heidelberg Institute for Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), UKHD and DKFZ, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

Vivek Verma (V)

Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center Houston, Houston, TX, USA.

Melanie Bewerunge-Hudler (M)

Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.

Andreas Unterberg (A)

German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
Department of Neurosurgery, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.

Dominik Sturm (D)

Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Angelika Lautenschläger Children's Hospital, University Medical Center for Children and Adolescents, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.

Christine Jungk (C)

German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
Department of Neurosurgery, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.

Christel Herold-Mende (C)

German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.

Wolfgang Wick (W)

German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
Department of Neurooncology, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.

Andreas von Deimling (A)

German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
Department of Neuropathology, University Hospital of Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

Juergen Debus (J)

German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Radiation Oncology, Heidelberg University Hospital (UKHD), Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Heidelberg Institute for Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), UKHD and DKFZ, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

Stefan Rieken (S)

German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Radiation Oncology, Heidelberg University Hospital (UKHD), Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Heidelberg Institute for Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), UKHD and DKFZ, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

Amir Abdollahi (A)

German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Radiation Oncology, Heidelberg University Hospital (UKHD), Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Heidelberg Institute for Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), UKHD and DKFZ, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › DNA-methylome-assisted classification of...
questionsmedicales.fr › Maladies du système nerveux › Tumeurs du système nerveux › Tumeurs du système nerveux central › Tumeurs du cerveau › DNA-methylome-assisted classification of...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Variation structurale du génome › Variations de nombre de copies de segment d'ADN › DNA-methylome-assisted classification of...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Épigénome › DNA-methylome-assisted classification of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de l'oeil › DNA-methylome-assisted classification of...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroépitheliales › Gliome › Astrocytome › Glioblastome › DNA-methylome-assisted classification of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › DNA-methylome-assisted classification of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › DNA-methylome-assisted classification of...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Ventricules cérébraux › Ventricules latéraux › DNA-methylome-assisted classification of...
questionsmedicales.fr › Diagnostic › Pronostic › DNA-methylome-assisted classification of...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Études rétrospectives › DNA-methylome-assisted classification of...