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01-01-2021 | Glioblastoma | Original Paper

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

Authors: Abigail K. Suwala, Damian Stichel, Daniel Schrimpf, Matthias Kloor, Annika K. Wefers, Annekathrin Reinhardt, Sybren L. N. Maas, Christian P. Kratz, Leonille Schweizer, Martin Hasselblatt, Matija Snuderl, Malak Sameer J. Abedalthagafi, Zied Abdullaev, Camelia M. Monoranu, Markus Bergmann, Arnulf Pekrun, Christian Freyschlag, Eleonora Aronica, Christof M. Kramm, Felix Hinz, Philipp Sievers, Andrey Korshunov, Marcel Kool, Stefan M. Pfister, Dominik Sturm, David T. W. Jones, Wolfgang Wick, Andreas Unterberg, Christian Hartmann, Andrew Dodgshun, Uri Tabori, Pieter Wesseling, Felix Sahm, Andreas von Deimling, David E. Reuss

Published in: Acta Neuropathologica | Issue 1/2021

Abstract

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.

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Title: Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis
Authors: Abigail K. Suwala
Damian Stichel
Daniel Schrimpf
Matthias Kloor
Annika K. Wefers
Annekathrin Reinhardt
Sybren L. N. Maas
Christian P. Kratz
Leonille Schweizer
Martin Hasselblatt
Matija Snuderl
Malak Sameer J. Abedalthagafi
Zied Abdullaev
Camelia M. Monoranu
Markus Bergmann
Arnulf Pekrun
Christian Freyschlag
Eleonora Aronica
Christof M. Kramm
Felix Hinz
Philipp Sievers
Andrey Korshunov
Marcel Kool
Stefan M. Pfister
Dominik Sturm
David T. W. Jones
Wolfgang Wick
Andreas Unterberg
Christian Hartmann
Andrew Dodgshun
Uri Tabori
Pieter Wesseling
Felix Sahm
Andreas von Deimling
David E. Reuss
Publication date: 01-01-2021
Publisher: Springer Berlin Heidelberg
Keywords: Glioblastoma
Astrocytoma
Glioma
Glioma
Astrocytoma
Glioblastoma
Astrocytoma
Glioblastoma
Glioma
Published in: Acta Neuropathologica / Issue 1/2021
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-020-02243-6

At a glance: The STEP trials

Springer Medicine

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

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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