@article{b3eb653af50b4c9dba998bb00dda146e,
title = "Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis",
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.",
keywords = "ATRX, CMMRD, DNA methylation, Glioblastoma, IDH, Lynch, Mismatch repair, Prognosis, Subtype",
author = "Suwala, {Abigail K.} and Damian Stichel and Daniel Schrimpf and Matthias Kloor and Wefers, {Annika K.} and Annekathrin Reinhardt and Maas, {Sybren L. N.} and Kratz, {Christian P.} and Leonille Schweizer and Martin Hasselblatt and Matija Snuderl and Abedalthagafi, {Malak Sameer J.} and Zied Abdullaev and Monoranu, {Camelia M.} and Markus Bergmann and Arnulf Pekrun and Christian Freyschlag and Eleonora Aronica and Kramm, {Christof M.} and Felix Hinz and Philipp Sievers and Andrey Korshunov and Marcel Kool and Pfister, {Stefan M.} and Dominik Sturm and Jones, {David T. W.} and Wolfgang Wick and Andreas Unterberg and Christian Hartmann and Andrew Dodgshun and Uri Tabori and Pieter Wesseling and Felix Sahm and {von Deimling}, Andreas and Reuss, {David E.}",
note = "Funding Information: This work was supported by German Cancer Aid (70112371). AvD, DER, DTWJ, SMP, WW and FS were supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 1389). FS is fellow of the Else Kr?ner Excellence Program of the Else Kr?ner-Fresenius Stiftung (EKFS). LS is a fellow of the BIH?Charit? Clinical Scientist Program by the Charit? and BIH and supported by a DKTK Young Investigator grant. CPK and SMP have been supported by the Deutsche Kinderkrebsstiftung (DKS2017.02), and BMBF ADDRess (01GM1909A). Methylation profiling at NYU Langone Health was in part supported by grants from the Friedberg Charitable Foundation, the Making Headway Foundation and the Sohn Foundation (to M.S.). We would like to thank Ulrike Vogel, Sabrina Sprengart, Viktoria Zeller, Lisa Kreinbihl, Laura D?rner, Moritz Schalles, Lea Hofmann, Ulrike Lass and Jochen Meyer for excellent assistance and Marius Felix for proofreading of the manuscript. Funding Information: This work was supported by German Cancer Aid (70112371). AvD, DER, DTWJ, SMP, WW and FS were supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 1389). FS is fellow of the Else Kr{\"o}ner Excellence Program of the Else Kr{\"o}ner-Fresenius Stiftung (EKFS). LS is a fellow of the BIH‐Charit{\'e} Clinical Scientist Program by the Charit{\'e} and BIH and supported by a DKTK Young Investigator grant. CPK and SMP have been supported by the Deutsche Kinderkrebsstiftung (DKS2017.02), and BMBF ADDRess (01GM1909A). Methylation profiling at NYU Langone Health was in part supported by grants from the Friedberg Charitable Foundation, the Making Headway Foundation and the Sohn Foundation (to M.S.). We would like to thank Ulrike Vogel, Sabrina Sprengart, Viktoria Zeller, Lisa Kreinbihl, Laura D{\"o}rner, Moritz Schalles, Lea Hofmann, Ulrike Lass and Jochen Meyer for excellent assistance and Marius Felix for proofreading of the manuscript. Publisher Copyright: {\textcopyright} 2020, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = jan,
doi = "https://doi.org/10.1007/s00401-020-02243-6",
language = "English",
volume = "141",
pages = "85--100",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",
number = "1",
}