{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T23:47:10Z","timestamp":1791589630973,"version":"4.3.4"},"reference-count":52,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,11,20]],"date-time":"2020-11-20T00:00:00Z","timestamp":1605830400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,11,20]],"date-time":"2020-11-20T00:00:00Z","timestamp":1605830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["70112371"],"award-info":[{"award-number":["70112371"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018936","name":"Universit\u00e4tsklinikum Heidelberg","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100018936","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Neuropathol"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    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\u00a0years). Mismatch repair deficiency syndromes (Lynch or Constitutional Mismatch Repair Deficiency Syndrom (CMMRD)) were clinically diagnosed and\/or germline mutations in DNA mismatch repair genes (\n                    <jats:italic>MLH1<\/jats:italic>\n                    ,\n                    <jats:italic>MSH6<\/jats:italic>\n                    ,\n                    <jats:italic>MSH2<\/jats:italic>\n                    ) 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\n                    <jats:italic>TP53<\/jats:italic>\n                    ,\n                    <jats:italic>RB1<\/jats:italic>\n                    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\n                    <jats:italic>MGMT<\/jats:italic>\n                    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\u00a0months 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.\n                  <\/jats:p>","DOI":"10.1007\/s00401-020-02243-6","type":"journal-article","created":{"date-parts":[[2020,11,20]],"date-time":"2020-11-20T07:03:53Z","timestamp":1605855833000},"page":"85-100","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":102,"title":["Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis"],"prefix":"10.1007","volume":"141","author":[{"given":"Abigail K.","family":"Suwala","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damian","family":"Stichel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Schrimpf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Kloor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika K.","family":"Wefers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annekathrin","family":"Reinhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sybren L. N.","family":"Maas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian P.","family":"Kratz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonille","family":"Schweizer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Hasselblatt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matija","family":"Snuderl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malak Sameer J.","family":"Abedalthagafi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zied","family":"Abdullaev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camelia M.","family":"Monoranu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Bergmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnulf","family":"Pekrun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Freyschlag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Aronica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christof M.","family":"Kramm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Hinz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Sievers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrey","family":"Korshunov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Kool","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan M.","family":"Pfister","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Sturm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David T. W.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Wick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Unterberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Hartmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Dodgshun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uri","family":"Tabori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter","family":"Wesseling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Sahm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"von Deimling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4573-6033","authenticated-orcid":false,"given":"David E.","family":"Reuss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,20]]},"reference":[{"key":"2243_CR1","doi-asserted-by":"publisher","first-page":"2402","DOI":"10.1200\/jco.2017.73.0119","volume":"35","author":"BM Alexander","year":"2017","unstructured":"Alexander BM, Cloughesy TF (2017) Adult Glioblastoma. J Clin Oncol 35:2402\u20132409. https:\/\/doi.org\/10.1200\/jco.2017.73.0119","journal-title":"J Clin Oncol"},{"key":"2243_CR2","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1007\/s00401-012-1016-2","volume":"124","author":"P Bady","year":"2012","unstructured":"Bady P, Sciuscio D, Diserens AC, Bloch J, van den Bent MJ, Marosi C, Dietrich PY, Weller M, Mariani L, Heppner FL et al (2012) MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status. Acta Neuropathol 124:547\u2013560. https:\/\/doi.org\/10.1007\/s00401-012-1016-2","journal-title":"Acta Neuropathol"},{"key":"2243_CR3","doi-asserted-by":"publisher","first-page":"4740","DOI":"10.1038\/s41467-020-18514-5","volume":"11","author":"A Ballhausen","year":"2020","unstructured":"Ballhausen A, Przybilla MJ, Jendrusch M, Haupt S, Pfaffendorf E, Seidler F, Witt J, Hernandez Sanchez A, Urban K, Draxlbauer M et al (2020) The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution. Nat Commun 11:4740. https:\/\/doi.org\/10.1038\/s41467-020-18514-5","journal-title":"Nat Commun"},{"key":"2243_CR4","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1007\/s00401-008-0455-2","volume":"116","author":"J Balss","year":"2008","unstructured":"Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A (2008) Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116:597\u2013602. https:\/\/doi.org\/10.1007\/s00401-008-0455-2","journal-title":"Acta Neuropathol"},{"key":"2243_CR5","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-020-02194-y","volume-title":"Infratentorial IDH-mutant astrocytoma is a distinct subtype","author":"R Banan","year":"2020","unstructured":"Banan R, Stichel D, Bleck A, Hong B, Lehmann U, Suwala A, Reinhardt A, Schrimpf D, Buslei R, Stadelmann C et al (2020) Infratentorial IDH-mutant astrocytoma is a distinct subtype. Doi, Acta neuropathologica. https:\/\/doi.org\/10.1007\/s00401-020-02194-y"},{"key":"2243_CR6","doi-asserted-by":"publisher","first-page":"2206","DOI":"10.1200\/JCO.2016.66.6552","volume":"34","author":"E Bouffet","year":"2016","unstructured":"Bouffet E, Larouche V, Campbell BB, Merico D, de Borja R, Aronson M, Durno C, Krueger J, Cabric V, Ramaswamy V et al (2016) Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol 34:2206\u20132211. https:\/\/doi.org\/10.1200\/JCO.2016.66.6552","journal-title":"J Clin Oncol"},{"key":"2243_CR7","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1007\/s00401-020-02127-9","volume":"139","author":"DJ Brat","year":"2020","unstructured":"Brat DJ, Aldape K, Colman H, Figrarella-Branger D, Fuller GN, Giannini C, Holland EC, Jenkins RB, Kleinschmidt-DeMasters B, Komori T et al (2020) cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol 139:603\u2013608. https:\/\/doi.org\/10.1007\/s00401-020-02127-9","journal-title":"Acta Neuropathol"},{"key":"2243_CR8","doi-asserted-by":"publisher","first-page":"1344","DOI":"10.1056\/NEJMoa1500925","volume":"374","author":"JC Buckner","year":"2016","unstructured":"Buckner JC, Shaw EG, Pugh SL, Chakravarti A, Gilbert MR, Barger GR, Coons S, Ricci P, Bullard D, Brown PD et al (2016) Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med 374:1344\u20131355. https:\/\/doi.org\/10.1056\/NEJMoa1500925","journal-title":"N Engl J Med"},{"key":"2243_CR9","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1038\/s41591-018-0095-6","volume":"24","author":"L Bunse","year":"2018","unstructured":"Bunse L, Pusch S, Bunse T, Sahm F, Sanghvi K, Friedrich M, Alansary D, Sonner JK, Green E, Deumelandt K et al (2018) Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat Med 24:1192\u20131203. https:\/\/doi.org\/10.1038\/s41591-018-0095-6","journal-title":"Nat Med"},{"key":"2243_CR10","doi-asserted-by":"publisher","first-page":"2038","DOI":"10.1158\/1078-0432.CCR-06-2149","volume":"13","author":"DP Cahill","year":"2007","unstructured":"Cahill DP, Levine KK, Betensky RA, Codd PJ, Romany CA, Reavie LB, Batchelor TT, Futreal PA, Stratton MR, Curry WT et al (2007) Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clin Cancer Res 13:2038\u20132045. https:\/\/doi.org\/10.1158\/1078-0432.CCR-06-2149","journal-title":"Clin Cancer Res"},{"key":"2243_CR11","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1016\/j.cell.2017.09.048","volume":"171","author":"BB Campbell","year":"2017","unstructured":"Campbell BB, Light N, Fabrizio D, Zatzman M, Fuligni F, de Borja R, Davidson S, Edwards M, Elvin JA, Hodel KP et al (2017a) Comprehensive analysis of hypermutation in human cancer. Cell 171:1042-1056.e1010. https:\/\/doi.org\/10.1016\/j.cell.2017.09.048","journal-title":"Cell"},{"issue":"1042\u20131056","key":"2243_CR12","doi-asserted-by":"publisher","first-page":"e1010","DOI":"10.1016\/j.cell.2017.09.048","volume":"171","author":"BB Campbell","year":"2017","unstructured":"Campbell BB, Light N, Fabrizio D, Zatzman M, Fuligni F, de Borja R, Davidson S, Edwards M, Elvin JA, Hodel KP et al (2017b) Comprehensive analysis of hypermutation in human cancer. Cell 171(1042\u20131056):e1010. https:\/\/doi.org\/10.1016\/j.cell.2017.09.048","journal-title":"Cell"},{"key":"2243_CR13","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1038\/nature07385","volume":"455","author":"Cancer Genome Atlas Research N","year":"2008","unstructured":"Cancer Genome Atlas Research N (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061\u20131068. https:\/\/doi.org\/10.1038\/nature07385","journal-title":"Nature"},{"key":"2243_CR14","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1038\/nature26000","volume":"555","author":"D Capper","year":"2018","unstructured":"Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D, Koelsche C, Sahm F, Chavez L, Reuss DE et al (2018) DNA methylation-based classification of central nervous system tumours. Nature 555:469\u2013474. https:\/\/doi.org\/10.1038\/nature26000","journal-title":"Nature"},{"key":"2243_CR15","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1111\/j.1750-3639.2009.00352.x","volume":"20","author":"D Capper","year":"2010","unstructured":"Capper D, Weissert S, Balss J, Habel A, Meyer J, Jager D, Ackermann U, Tessmer C, Korshunov A, Zentgraf H et al (2010) Characterization of R132H mutation-specific IDH1 antibody binding in brain tumors. Brain Pathol 20:245\u2013254. https:\/\/doi.org\/10.1111\/j.1750-3639.2009.00352.x","journal-title":"Brain Pathol"},{"key":"2243_CR16","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s13073-017-0424-2","volume":"9","author":"ZR Chalmers","year":"2017","unstructured":"Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, Schrock A, Campbell B, Shlien A, Chmielecki J et al (2017) Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 9:34. https:\/\/doi.org\/10.1186\/s13073-017-0424-2","journal-title":"Genome Med"},{"key":"2243_CR17","doi-asserted-by":"publisher","first-page":"1300","DOI":"10.1093\/neuonc\/noy016","volume":"20","author":"S Choi","year":"2018","unstructured":"Choi S, Yu Y, Grimmer MR, Wahl M, Chang SM, Costello JF (2018) Temozolomide-associated hypermutation in gliomas. Neuro Oncol 20:1300\u20131309. https:\/\/doi.org\/10.1093\/neuonc\/noy016","journal-title":"Neuro Oncol"},{"key":"2243_CR18","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-020-02209-8","author":"AJ Dodgshun","year":"2020","unstructured":"Dodgshun AJ, Fukuoka K, Edwards M, Bianchi VJ, Das A, Sexton-Oates A, Larouche V, Vanan MI, Lindhorst S, Yalon M et al (2020) Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns. Acta Neuropathol. https:\/\/doi.org\/10.1007\/s00401-020-02209-8","journal-title":"Acta Neuropathol"},{"key":"2243_CR19","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.mrrev.2016.05.005","volume":"769","author":"H Erasimus","year":"2016","unstructured":"Erasimus H, Gobin M, Niclou S, Van Dyck E (2016) DNA repair mechanisms and their clinical impact in glioblastoma. Mutat Res Rev Mutat Res 769:19\u201335. https:\/\/doi.org\/10.1016\/j.mrrev.2016.05.005","journal-title":"Mutat Res Rev Mutat Res"},{"key":"2243_CR20","doi-asserted-by":"publisher","first-page":"8072","DOI":"10.1158\/0008-5472.can-04-4146","volume":"65","author":"P Findeisen","year":"2005","unstructured":"Findeisen P, Kloor M, Merx S, Sutter C, Woerner SM, Dostmann N, Benner A, Dondog B, Pawlita M, Dippold W et al (2005) T25 repeat in the 3\u2019 untranslated region of the CASP2 gene: a sensitive and specific marker for microsatellite instability in colorectal cancer. Can Res 65:8072\u20138078. https:\/\/doi.org\/10.1158\/0008-5472.can-04-4146","journal-title":"Can Res"},{"key":"2243_CR21","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1038\/nature16490","volume":"529","author":"WA Flavahan","year":"2016","unstructured":"Flavahan WA, Drier Y, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, Suva ML, Bernstein BE (2016) Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529:110\u2013114. https:\/\/doi.org\/10.1038\/nature16490","journal-title":"Nature"},{"key":"2243_CR22","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1111\/nan.12450","volume":"44","author":"F Galuppini","year":"2018","unstructured":"Galuppini F, Opocher E, Tabori U, Mammi I, Edwards M, Campbell B, Kelly J, Viel A, Quaia M, Rivieri F et al (2018) Concomitant IDH wild-type glioblastoma and IDH1-mutant anaplastic astrocytoma in a patient with constitutional mismatch repair deficiency syndrome. Neuropathol Appl Neurobiol 44:233\u2013239. https:\/\/doi.org\/10.1111\/nan.12450","journal-title":"Neuropathol Appl Neurobiol"},{"key":"2243_CR23","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1158\/2159-8290.CD-18-0469","volume":"9","author":"X Gong","year":"2019","unstructured":"Gong X, Du J, Parsons SH, Merzoug FF, Webster Y, Iversen PW, Chio LC, Van Horn RD, Lin X, Blosser W et al (2019) Aurora A kinase inhibition is synthetic lethal with loss of the RB1 tumor suppressor gene. Cancer Discov 9:248\u2013263. https:\/\/doi.org\/10.1158\/2159-8290.CD-18-0469","journal-title":"Cancer Discov"},{"key":"2243_CR24","doi-asserted-by":"publisher","first-page":"vdz033","DOI":"10.1093\/noajnl\/vdz033","volume":"1","author":"L Guerrini-Rousseau","year":"2019","unstructured":"Guerrini-Rousseau L, Varlet P, Colas C, Andreiuolo F, Bourdeaut F, Dahan K, Devalck C, Faure-Conter C, Genuardi M, Goldberg Y et al (2019) Constitutional mismatch repair deficiency-associated brain tumors: report from the European C4CMMRD consortium. Neurooncol Adv 1:vdz033. https:\/\/doi.org\/10.1093\/noajnl\/vdz033","journal-title":"Neurooncol Adv"},{"key":"2243_CR25","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1007\/s00401-009-0561-9","volume":"118","author":"C Hartmann","year":"2009","unstructured":"Hartmann C, Meyer J, Balss J, Capper D, Mueller W, Christians A, Felsberg J, Wolter M, Mawrin C, Wick W et al (2009) Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1010 diffuse gliomas. Acta Neuropathol 118:469\u2013474. https:\/\/doi.org\/10.1007\/s00401-009-0561-9","journal-title":"Acta Neuropathol"},{"key":"2243_CR26","doi-asserted-by":"publisher","first-page":"1690","DOI":"10.1158\/1078-0432.CCR-19-2000","volume":"26","author":"F Higuchi","year":"2020","unstructured":"Higuchi F, Nagashima H, Ning J, Koerner MVA, Wakimoto H, Cahill DP (2020) Restoration of temozolomide sensitivity by PARP inhibitors in mismatch repair deficient glioblastoma is independent of base excision repair. Clin Cancer Res 26:1690\u20131699. https:\/\/doi.org\/10.1158\/1078-0432.CCR-19-2000","journal-title":"Clin Cancer Res"},{"key":"2243_CR27","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/s41431-019-0527-x","volume":"28","author":"AML Jansen","year":"2020","unstructured":"Jansen AML, Tops CMJ, Ruano D, van Eijk R, Wijnen JT, Ten Broeke S, Nielsen M, Hes FJ, van Wezel T, Morreau H (2020) The complexity of screening PMS2 in DNA isolated from formalin-fixed paraffin-embedded material. Eur J Hum Genet 28:333\u2013338. https:\/\/doi.org\/10.1038\/s41431-019-0527-x","journal-title":"Eur J Hum Genet"},{"key":"2243_CR28","doi-asserted-by":"publisher","first-page":"1230","DOI":"10.1158\/2159-8290.CD-16-0575","volume":"6","author":"TM Johanns","year":"2016","unstructured":"Johanns TM, Miller CA, Dorward IG, Tsien C, Chang E, Perry A, Uppaluri R, Ferguson C, Schmidt RE, Dahiya S et al (2016) Immunogenomics of hypermutated glioblastoma: a patient with germline POLE deficiency treated with checkpoint blockade immunotherapy. Cancer Discov 6:1230\u20131236. https:\/\/doi.org\/10.1158\/2159-8290.CD-16-0575","journal-title":"Cancer Discov"},{"key":"2243_CR29","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1007\/s00401-020-02124-y","volume":"139","author":"B Kim","year":"2020","unstructured":"Kim B, Tabori U, Hawkins C (2020) An update on the CNS manifestations of brain tumor polyposis syndromes. Acta Neuropathol 139:703\u2013715. https:\/\/doi.org\/10.1007\/s00401-020-02124-y","journal-title":"Acta Neuropathol"},{"key":"2243_CR30","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.trecan.2016.02.004","volume":"2","author":"M Kloor","year":"2016","unstructured":"Kloor M, von Knebel DM (2016) The immune biology of microsatellite-unstable cancer. Trends Cancer 2:121\u2013133. https:\/\/doi.org\/10.1016\/j.trecan.2016.02.004","journal-title":"Trends Cancer"},{"key":"2243_CR31","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1111\/nan.12523","volume":"45","author":"A Korshunov","year":"2019","unstructured":"Korshunov A, Casalini B, Chavez L, Hielscher T, Sill M, Ryzhova M, Sharma T, Schrimpf D, Stichel D, Capper D et al (2019) Integrated molecular characterization of IDH-mutant glioblastomas. Neuropathol Appl Neurobiol 45:108\u2013118. https:\/\/doi.org\/10.1111\/nan.12523","journal-title":"Neuropathol Appl Neurobiol"},{"key":"2243_CR32","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1016\/S0140-6736(18)30990-5","volume":"392","author":"S Lapointe","year":"2018","unstructured":"Lapointe S, Perry A, Butowski NA (2018) Primary brain tumours in adults. Lancet 392:432\u2013446. https:\/\/doi.org\/10.1016\/S0140-6736(18)30990-5","journal-title":"Lancet"},{"key":"2243_CR33","doi-asserted-by":"publisher","first-page":"2509","DOI":"10.1056\/NEJMoa1500596","volume":"372","author":"DT Le","year":"2015","unstructured":"Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509\u20132520. https:\/\/doi.org\/10.1056\/NEJMoa1500596","journal-title":"N Engl J Med"},{"key":"2243_CR34","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1038\/s41580-018-0015-0","volume":"19","author":"YR Lee","year":"2018","unstructured":"Lee YR, Chen M, Pandolfi PP (2018) The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol 19:547\u2013562. https:\/\/doi.org\/10.1038\/s41580-018-0015-0","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2243_CR35","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1007\/s00401-016-1545-1","volume":"131","author":"DN Louis","year":"2016","unstructured":"Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW (2016) The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 131:803\u2013820. https:\/\/doi.org\/10.1007\/s00401-016-1545-1","journal-title":"Acta Neuropathol"},{"key":"2243_CR36","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s40478-020-0892-2","volume":"8","author":"M McCord","year":"2020","unstructured":"McCord M, Steffens A, Javier R, Kam KL, McCortney K, Horbinski C (2020) The efficacy of DNA mismatch repair enzyme immunohistochemistry as a screening test for hypermutated gliomas. Acta Neuropathol Commun 8:15. https:\/\/doi.org\/10.1186\/s40478-020-0892-2","journal-title":"Acta Neuropathol Commun"},{"key":"2243_CR37","doi-asserted-by":"publisher","first-page":"1807","DOI":"10.1126\/science.1164382","volume":"321","author":"DW Parsons","year":"2008","unstructured":"Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807\u20131812. https:\/\/doi.org\/10.1126\/science.1164382","journal-title":"Science"},{"key":"2243_CR38","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.ejca.2019.12.029","volume":"127","author":"ADJ Pearson","year":"2020","unstructured":"Pearson ADJ, Rossig C, Lesa G, Diede SJ, Weiner S, Anderson J, Gray J, Geoerger B, Minard-Colin V, Marshall LV et al (2020) ACCELERATE and European Medicines Agency Paediatric Strategy Forum for medicinal product development of checkpoint inhibitors for use in combination therapy in paediatric patients. Eur J Cancer 127:52\u201366. https:\/\/doi.org\/10.1016\/j.ejca.2019.12.029","journal-title":"Eur J Cancer"},{"key":"2243_CR39","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1007\/s00401-017-1677-y","volume":"133","author":"S Pusch","year":"2017","unstructured":"Pusch S, Krausert S, Fischer V, Balss J, Ott M, Schrimpf D, Capper D, Sahm F, Eisel J, Beck AC et al (2017) Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo. Acta Neuropathol 133:629\u2013644. https:\/\/doi.org\/10.1007\/s00401-017-1677-y","journal-title":"Acta Neuropathol"},{"key":"2243_CR40","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/nrc3911","volume":"15","author":"N Ratner","year":"2015","unstructured":"Ratner N, Miller SJ (2015) A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer 15:290\u2013301. https:\/\/doi.org\/10.1038\/nrc3911","journal-title":"Nat Rev Cancer"},{"key":"2243_CR41","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1038\/sj.onc.1209785","volume":"26","author":"WP Roos","year":"2007","unstructured":"Roos WP, Batista LF, Naumann SC, Wick W, Weller M, Menck CF, Kaina B (2007) Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine. Oncogene 26:186\u2013197. https:\/\/doi.org\/10.1038\/sj.onc.1209785","journal-title":"Oncogene"},{"key":"2243_CR42","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1007\/s00401-015-1519-8","volume":"131","author":"F Sahm","year":"2016","unstructured":"Sahm F, Schrimpf D, Jones DT, Meyer J, Kratz A, Reuss D, Capper D, Koelsche C, Korshunov A, Wiestler B et al (2016) Next-generation sequencing in routine brain tumor diagnostics enables an integrated diagnosis and identifies actionable targets. Acta Neuropathol 131:903\u2013910. https:\/\/doi.org\/10.1007\/s00401-015-1519-8","journal-title":"Acta Neuropathol"},{"key":"2243_CR43","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/s1470-2045(09)70025-7","volume":"10","author":"R Stupp","year":"2009","unstructured":"Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459\u2013466. https:\/\/doi.org\/10.1016\/s1470-2045(09)70025-7","journal-title":"Lancet Oncol"},{"key":"2243_CR44","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1038\/s41586-020-2209-9","volume":"580","author":"M Touat","year":"2020","unstructured":"Touat M, Li YY, Boynton AN, Spurr LF, Iorgulescu JB, Bohrson CL, Cortes-Ciriano I, Birzu C, Geduldig JE, Pelton K et al (2020) Mechanisms and therapeutic implications of hypermutation in gliomas. Nature 580:517\u2013523. https:\/\/doi.org\/10.1038\/s41586-020-2209-9","journal-title":"Nature"},{"key":"2243_CR45","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1038\/nature10866","volume":"483","author":"S Turcan","year":"2012","unstructured":"Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, Campos C, Fabius AW, Lu C, Ward PS et al (2012) IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483:479\u2013483. https:\/\/doi.org\/10.1038\/nature10866","journal-title":"Nature"},{"key":"2243_CR46","doi-asserted-by":"publisher","first-page":"1645","DOI":"10.1016\/S0140-6736(17)31442-3","volume":"390","author":"MJ van den Bent","year":"2017","unstructured":"van den Bent MJ, Baumert B, Erridge SC, Vogelbaum MA, Nowak AK, Sanson M, Brandes AA, Clement PM, Baurain JF, Mason WP et al (2017) Interim results from the CATNON trial (EORTC study 26053\u201322054) of treatment with concurrent and adjuvant temozolomide for 1p\/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet 390:1645\u20131653. https:\/\/doi.org\/10.1016\/S0140-6736(17)31442-3","journal-title":"Lancet"},{"key":"2243_CR47","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1007\/s00401-015-1403-6","volume":"129","author":"HF van Thuijl","year":"2015","unstructured":"van Thuijl HF, Mazor T, Johnson BE, Fouse SD, Aihara K, Hong C, Malmstr\u00f6m A, Hallbeck M, Heimans JJ, Kloezeman JJ et al (2015) Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment. Acta Neuropathol 129:597\u2013607. https:\/\/doi.org\/10.1007\/s00401-015-1403-6","journal-title":"Acta Neuropathol"},{"key":"2243_CR48","doi-asserted-by":"publisher","first-page":"15017","DOI":"10.1038\/nrdp.2015.17","volume":"1","author":"M Weller","year":"2015","unstructured":"Weller M, Wick W, Aldape K, Brada M, Berger M, Pfister SM, Nishikawa R, Rosenthal M, Wen PY, Stupp R et al (2015) Glioma. Nat Rev Dis Primers 1:15017. https:\/\/doi.org\/10.1038\/nrdp.2015.17","journal-title":"Nat Rev Dis Primers"},{"key":"2243_CR49","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1093\/neuonc\/noy161","volume":"21","author":"W Wick","year":"2019","unstructured":"Wick W, Dettmer S, Berberich A, Kessler T, Karapanagiotou-Schenkel I, Wick A, Winkler F, Pfaff E, Brors B, Debus J et al (2019) N2M2 (NOA-20) phase I\/II trial of molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed non-MGMT hypermethylated glioblastoma. Neuro Oncol 21:95\u2013105. https:\/\/doi.org\/10.1093\/neuonc\/noy161","journal-title":"Neuro Oncol"},{"key":"2243_CR50","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1007\/s00401-014-1315-x","volume":"128","author":"B Wiestler","year":"2014","unstructured":"Wiestler B, Capper D, Sill M, Jones DT, Hovestadt V, Sturm D, Koelsche C, Bertoni A, Schweizer L, Korshunov A et al (2014) Integrated DNA methylation and copy-number profiling identify three clinically and biologically relevant groups of anaplastic glioma. Acta Neuropathol 128:561\u2013571. https:\/\/doi.org\/10.1007\/s00401-014-1315-x","journal-title":"Acta Neuropathol"},{"key":"2243_CR51","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1056\/NEJMoa0808710","volume":"360","author":"H Yan","year":"2009","unstructured":"Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765\u2013773. https:\/\/doi.org\/10.1056\/NEJMoa0808710","journal-title":"N Engl J Med"},{"key":"2243_CR52","doi-asserted-by":"publisher","first-page":"2075","DOI":"10.1111\/jcmm.12618","volume":"19","author":"J Zhang","year":"2015","unstructured":"Zhang J, Zhang F, Niu R (2015) Functions of Shp2 in cancer. J Cell Mol Med 19:2075\u20132083. https:\/\/doi.org\/10.1111\/jcmm.12618","journal-title":"J Cell Mol Med"}],"container-title":["Acta Neuropathologica"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-020-02243-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s00401-020-02243-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-020-02243-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,5]],"date-time":"2021-01-05T13:36:41Z","timestamp":1609853801000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s00401-020-02243-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,20]]},"references-count":52,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,1]]}},"alternative-id":["2243"],"URL":"https:\/\/doi.org\/10.1007\/s00401-020-02243-6","relation":{},"ISSN":["0001-6322","1432-0533"],"issn-type":[{"value":"0001-6322","type":"print"},{"value":"1432-0533","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,20]]},"assertion":[{"value":"23 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 October 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 November 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 November 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}]}}