Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis
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ORIGINAL PAPER
Primary mismatch repair deficient IDH‑mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis Abigail K. Suwala1,2 · Damian Stichel2 · Daniel Schrimpf1,2 · Matthias Kloor3,4,5 · Annika K. Wefers1,2 · Annekathrin Reinhardt1,2 · Sybren L. N. Maas1,6 · Christian P. Kratz7 · Leonille Schweizer8,9 · Martin Hasselblatt10 · Matija Snuderl11,12,13 · Malak Sameer J. Abedalthagafi14,15 · Zied Abdullaev16 · Camelia M. Monoranu17 · Markus Bergmann18 · Arnulf Pekrun19 · Christian Freyschlag20 · Eleonora Aronica21 · Christof M. Kramm22 · Felix Hinz1,2 · Philipp Sievers1,2 · Andrey Korshunov1,2 · Marcel Kool23,24,25 · Stefan M. Pfister23,24,26 · Dominik Sturm23,24,26 · David T. W. Jones23,27 · Wolfgang Wick28,29 · Andreas Unterberg30 · Christian Hartmann31 · Andrew Dodgshun32,33 · Uri Tabori34,35,36 · Pieter Wesseling25,37 · Felix Sahm1,2,23 · Andreas von Deimling1,2 · David E. Reuss1,2 Received: 23 September 2020 / Revised: 30 October 2020 / Accepted: 4 November 2020 © The Author(s) 2020
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 IDHmutant 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 highgrade 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 fe
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