Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis.

Adolescent Adult Astrocytoma / diagnosis Brain Neoplasms / diagnosis Child DNA Methylation DNA Mismatch Repair / genetics Female Gene Dosage Gene Expression Regulation, Neoplastic / genetics Humans Immunohistochemistry Isocitrate Dehydrogenase / genetics Kaplan-Meier Estimate Male Microsatellite Instability Mutation / genetics Neoplasm Recurrence, Local Prognosis Signal Transduction / genetics Survival Analysis X-linked Nuclear Protein / genetics Young Adult
ATRX CMMRD DNA methylation Glioblastoma IDH Lynch Mismatch repair Prognosis Subtype

Journal

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

Informations de publication

Date de publication:
01 2021
Historique:
received: 23 09 2020
accepted: 04 11 2020
revised: 30 10 2020
pubmed: 21 11 2020
medline: 26 10 2021
entrez: 20 11 2020
Statut: ppublish

Résumé

Diffuse IDH-mutant astrocytoma mostly occurs in adults and carries a favorable prognosis compared to IDH-wildtype malignant gliomas. Acquired mismatch repair deficiency is known to occur in recurrent IDH-mutant gliomas as resistance mechanism towards alkylating chemotherapy. In this multi-institutional study, we report a novel epigenetic group of 32 IDH-mutant gliomas with proven or suspected hereditary mismatch repair deficiency. None of the tumors exhibited a combined 1p/19q deletion. These primary mismatch repair-deficient IDH-mutant astrocytomas (PMMRDIA) were histologically high-grade and were mainly found in children, adolescents and young adults (median age 14 years). Mismatch repair deficiency syndromes (Lynch or Constitutional Mismatch Repair Deficiency Syndrom (CMMRD)) were clinically diagnosed and/or germline mutations in DNA mismatch repair genes (MLH1, MSH6, MSH2) were found in all cases, except one case with a family and personal history of colon cancer and another case with MSH6-deficiency available only as recurrent tumor. Loss of at least one of the mismatch repair proteins was detected via immunohistochemistry in all, but one case analyzed. Tumors displayed a hypermutant genotype and microsatellite instability was present in more than half of the sequenced cases. Integrated somatic mutational and chromosomal copy number analyses showed frequent inactivation of TP53, RB1 and activation of RTK/PI3K/AKT pathways. In contrast to the majority of IDH-mutant gliomas, more than 60% of the samples in our cohort presented with an unmethylated MGMT promoter. While the rate of immuno-histochemical ATRX loss was reduced, variants of unknown significance were more frequently detected possibly indicating a higher frequency of ATRX inactivation by protein malfunction. Compared to reference cohorts of other IDH-mutant gliomas, primary mismatch repair-deficient IDH-mutant astrocytomas have by far the worst clinical outcome with a median survival of only 15 months irrespective of histological or molecular features. The findings reveal a so far unknown entity of IDH-mutant astrocytoma with high prognostic relevance. Diagnosis can be established by aligning with the characteristic DNA methylation profile, by DNA-sequencing-based proof of mismatch repair deficiency or immunohistochemically demonstrating loss-of-mismatch repair proteins.

Identifiants

DOI: 10.1007/s00401-020-02243-6 PMID: 33216206 PMC: PMC7785563
pubmed: 33216206
doi: 10.1007/s00401-020-02243-6
pii: 10.1007/s00401-020-02243-6
pmc: PMC7785563
doi:

Substances chimiques

Isocitrate Dehydrogenase EC 1.1.1.41
ATRX protein, human EC 3.6.4.12
X-linked Nuclear Protein EC 3.6.4.12

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

85-100

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Auteurs

Abigail K Suwala (AK)

Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.

Damian Stichel (D)

Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.

Daniel Schrimpf (D)

Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.

Matthias Kloor (M)

Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, European Molecular Biology Laboratory, Heidelberg, Germany.

Annika K Wefers (AK)

Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.

Annekathrin Reinhardt (A)

Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.

Sybren L N Maas (SLN)

Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Christian P Kratz (CP)

Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.

Leonille Schweizer (L)

Department of Neuropathology, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin, Germany.
German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Martin Hasselblatt (M)

Institute of Neuropathology, University Hospital Münster, Münster, Germany.

Matija Snuderl (M)

Division of Neuropathology, NYU Langone Health, New York, USA.
Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, USA.
Division of Molecular Pathology and Diagnostics, NYU Langone Health, New York, USA.

Malak Sameer J Abedalthagafi (MSJ)

Pathology Department, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.

Zied Abdullaev (Z)

Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Camelia M Monoranu (CM)

Institute of Pathology, Julius-Maximilians-University, Würzburg, Germany.

Markus Bergmann (M)

Institute of Clinical Neuropathology, Bremen-Mitte Medical Center, Bremen, Germany.

Arnulf Pekrun (A)

Professor Hess Children's Hospital, Klinikum Bremen-Mitte, Bremen, Germany.

Christian Freyschlag (C)

Department of Neurosurgery, Medical University of Innsbruck, Innsbruck, Austria.

Eleonora Aronica (E)

Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands.

Christof M Kramm (CM)

Division of Pediatric Hematology and Oncology, University Medical Center Goettingen, Goettingen, Germany.

Felix Hinz (F)

Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.

Philipp Sievers (P)

Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.

Andrey Korshunov (A)

Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.

Marcel Kool (M)

Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Stefan M Pfister (SM)

Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany.

Dominik Sturm (D)

Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany.

David T W Jones (DTW)

Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
Pediatric Glioma Research Group, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Wolfgang Wick (W)

Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.

Andreas Unterberg (A)

Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany.

Christian Hartmann (C)

Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover, Germany.

Andrew Dodgshun (A)

Department of Paediatrics, University of Otago, Christchurch, New Zealand.
Children's Haematology and Oncology Center, Christchurch Hospital, Christchurch, New Zealand.

Uri Tabori (U)

The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
Division of Haematology and Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Canada.

Pieter Wesseling (P)

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Department of Pathology, Amsterdam University Medical Centers/VUmc and Brain Tumor Center Amsterdam, Amsterdam, The Netherlands.

Felix Sahm (F)

Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.

Andreas von Deimling (A)

Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.

David E Reuss (DE)

Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. david.reuss@med.uni-heidelberg.de.
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany. david.reuss@med.uni-heidelberg.de.
ORCID: 0000-0002-4573-6033

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Classifications MeSH

Recherchemedicale.com › Personnes › Tranches d'âge › Adolescent › Primary mismatch repair deficient IDH-mutant...
Recherchemedicale.com › Personnes › Tranches d'âge › Adulte › Primary mismatch repair deficient IDH-mutant...
Recherchemedicale.com › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroépitheliales › Gliome › Astrocytome › Primary mismatch repair deficient IDH-mutant...
Recherchemedicale.com › Maladies du système nerveux › Tumeurs du système nerveux › Tumeurs du système nerveux central › Tumeurs du cerveau › Primary mismatch repair deficient IDH-mutant...
Recherchemedicale.com › Personnes › Tranches d'âge › Enfant › Primary mismatch repair deficient IDH-mutant...
Recherchemedicale.com › Phénomènes génétiques › Méthylation de l'ADN › Primary mismatch repair deficient IDH-mutant...
Recherchemedicale.com › Phénomènes génétiques › Réparation de l'ADN › Réparation de mésappariement de l'ADN › Primary mismatch repair deficient IDH-mutant...
Recherchemedicale.com › Phénomènes génétiques › Génotype › Dosage génique › Primary mismatch repair deficient IDH-mutant...
Recherchemedicale.com › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Primary mismatch repair deficient IDH-mutant...
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Recherchemedicale.com › Disciplines des sciences naturelles › Chimie › Biochimie › Immunohistochimie › Primary mismatch repair deficient IDH-mutant...
Recherchemedicale.com › Enzymes et coenzymes › Enzymes › Oxidoreductases › Alcohol oxidoreductases › NAD (+) and NADP (+) dependent Alcohol oxidoreductases › Isocitrate dehydrogenases › Primary mismatch repair deficient IDH-mutant...
Recherchemedicale.com › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Analyse de survie › Estimation de Kaplan-Meier › Primary mismatch repair deficient IDH-mutant...
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Recherchemedicale.com › Phénomènes physiologiques cellulaires › Transduction du signal › Primary mismatch repair deficient IDH-mutant...
Recherchemedicale.com › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Analyse de survie › Primary mismatch repair deficient IDH-mutant...
Recherchemedicale.com › Enzymes et coenzymes › Enzymes › Isomerases › Helicase › Protéine nucléaire liée à l'X › Primary mismatch repair deficient IDH-mutant...
Recherchemedicale.com › Personnes › Tranches d'âge › Adulte › Jeune adulte › Primary mismatch repair deficient IDH-mutant...