{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T05:46:50Z","timestamp":1792043210528,"version":"4.4.0"},"reference-count":47,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,2,2]],"date-time":"2025-02-02T00:00:00Z","timestamp":1738454400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,2,2]],"date-time":"2025-02-02T00:00:00Z","timestamp":1738454400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100011835","name":"Nieders\u00e4chsische Krebsgesellschaft e.V.","doi-asserted-by":"crossref","award":["Advancement Award 2023"],"award-info":[{"award-number":["Advancement Award 2023"]}],"id":[{"id":"10.13039\/501100011835","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100011835","name":"Nieders\u00e4chsische Krebsgesellschaft e.V.","doi-asserted-by":"crossref","award":["Advancement Award 2023"],"award-info":[{"award-number":["Advancement Award 2023"]}],"id":[{"id":"10.13039\/501100011835","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100011835","name":"Nieders\u00e4chsische Krebsgesellschaft e.V.","doi-asserted-by":"crossref","award":["Advancement Award 2023"],"award-info":[{"award-number":["Advancement Award 2023"]}],"id":[{"id":"10.13039\/501100011835","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Medical Faculty of the University of Bonn, Bonn, Germany","award":["2022\u20131A-09"],"award-info":[{"award-number":["2022\u20131A-09"]}]},{"name":"German Federal Ministry of Education and Research","award":["01GM2205A"],"award-info":[{"award-number":["01GM2205A"]}]},{"DOI":"10.13039\/501100007311","name":"Deutsche Kinderkrebsstiftung","doi-asserted-by":"publisher","award":["DKS 2024.03"],"award-info":[{"award-number":["DKS 2024.03"]}],"id":[{"id":"10.13039\/501100007311","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Universit\u00e4tsklinikum Bonn"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Neuropathol"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Pediatric high-grade glioma (pedHGG) can occur as first manifestation of cancer predisposition syndromes resulting from pathogenic germline variants in the DNA mismatch repair (MMR) genes <jats:italic>MSH2<\/jats:italic>, <jats:italic>MSH6<\/jats:italic>, <jats:italic>MLH1<\/jats:italic>, and <jats:italic>PMS2<\/jats:italic>. The aim of this study was to establish a generalized screening for Lynch syndrome and constitutional MMR deficiency (CMMRD) in pedHGG patients, as the detection of MMR deficiencies (MMRD) may enable the upfront therapeutic use of checkpoint inhibitors and identification of variant carriers in the patients\u2019 families. We prospectively enrolled 155 centrally reviewed primary pedHGG patients for MMR-immunohistochemistry (IHC) as part of the HIT-HGG-2013 trial protocol. MMR-IHC results were subsequently compared to independently collected germline sequencing data (whole exome sequencing or pan-cancer DNA panel next-generation sequencing) available in the HIT-HGG-2013, INFORM, and MNP2.0 trials. MMR-IHC could be successfully performed in 127\/155 tumor tissues. The screening identified all present cases with Lynch syndrome or CMMRD (5.5%). In addition, MMR-IHC also detected cases with exclusive somatic MMR gene alterations (2.3%), including <jats:italic>MSH2<\/jats:italic> hypermethylation as an alternative epigenetic silencing mechanism. Most of the identified pedHGG MMRD patients had no family history of MMRD, and thus, they represented index patients in their families. Cases with regular protein expression in MMR-IHC never showed evidence for MMRD in DNA sequencing. In conclusion, MMR-IHC presents a cost-effective, relatively widely available, and fast screening method for germline MMRD in pedHGG with high sensitivity (100%) and specificity (96%). Given the relatively high prevalence of previously undetected MMRD cases among pedHGG patients, we strongly recommend incorporating MMR-IHC into routine diagnostics.<\/jats:p>","DOI":"10.1007\/s00401-025-02846-x","type":"journal-article","created":{"date-parts":[[2025,2,2]],"date-time":"2025-02-02T19:23:21Z","timestamp":1738524201000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["MSH2, MSH6, MLH1, and PMS2 immunohistochemistry as highly sensitive screening method for DNA mismatch repair deficiency syndromes in pediatric high-grade glioma"],"prefix":"10.1007","volume":"149","author":[{"given":"Lea L.","family":"Friker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Perwein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Waha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn","family":"D\u00f6rner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam","family":"Blattner-Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian P.","family":"Layer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Sturm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunther","family":"Nussbaumer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Kwiecien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Spier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Aretz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kornelius","family":"Kerl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Hennewig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marius","family":"Rohde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Karow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingmar","family":"Bluemcke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann Kristin","family":"Schmitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Reinhard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Hern\u00e1iz Driever","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Wendt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Weiser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana S.","family":"Guerreiro St\u00fccklin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas U.","family":"Gerber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9 O.","family":"von Bueren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Khurana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Jorch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Wiese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian P.","family":"Kratz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Eyrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Karremann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Herrlinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"H\u00f6lzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David T. W.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torsten","family":"Pietsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerrit H.","family":"Gielen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christof M.","family":"Kramm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,2]]},"reference":[{"key":"2846_CR1","doi-asserted-by":"publisher","first-page":"2521","DOI":"10.1007\/s00381-021-05229-1","volume":"37","author":"S Alphones","year":"2021","unstructured":"Alphones S, Chatterjee U, Singh A, Das A, Zameer L, Achari R et al (2021) Immunohistochemical screening for mismatch repair protein deficiency in paediatric high-grade gliomas - institutional experience and review of literature. Childs Nerv Syst 37:2521\u20132530. https:\/\/doi.org\/10.1007\/s00381-021-05229-1","journal-title":"Childs Nerv Syst"},{"key":"2846_CR2","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1002\/ijc.29724","volume":"138","author":"N Amayiri","year":"2016","unstructured":"Amayiri N, Tabori U, Campbell B, Bakry D, Aronson M, Durno C et al (2016) High frequency of mismatch repair deficiency among pediatric high grade gliomas in Jordan. Int J Cancer 138:380\u2013385. https:\/\/doi.org\/10.1002\/ijc.29724","journal-title":"Int J Cancer"},{"key":"2846_CR3","doi-asserted-by":"publisher","first-page":"1548","DOI":"10.12669\/pjms.39.5.6300","volume":"39","author":"F Bashir","year":"2023","unstructured":"Bashir F, Qureshi BM, Minhas K, Tabori U, Bouffet E, Hawkins C et al (2023) Pakistan national guidelines for pediatric high-grade gliomas. Pak J Med Sci Q 39:1548\u20131554. https:\/\/doi.org\/10.12669\/pjms.39.5.6300","journal-title":"Pak J Med Sci Q"},{"key":"2846_CR4","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 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":"2846_CR5","doi-asserted-by":"publisher","first-page":"2060","DOI":"10.3390\/genes14112060","volume":"14","author":"IW Carnevali","year":"2023","unstructured":"Carnevali IW, Cini G, Libera L, Sahnane N, Facchi S, Viel A et al (2023) MLH1 promoter methylation could be the second hit in lynch syndrome carcinogenesis. Genes 14:2060. https:\/\/doi.org\/10.3390\/genes14112060","journal-title":"Genes"},{"key":"2846_CR6","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1200\/JCO.21.02873","volume":"41","author":"J Chung","year":"2023","unstructured":"Chung J, Negm L, Bianchi V, Stengs L, Das A, Liu ZA et al (2023) Genomic microsatellite signatures identify germline mismatch repair deficiency and risk of cancer onset. J Clin Oncol 41:766\u2013777. https:\/\/doi.org\/10.1200\/JCO.21.02873","journal-title":"J Clin Oncol"},{"key":"2846_CR7","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.humpath.2020.07.001","volume":"103","author":"W Chen","year":"2020","unstructured":"Chen W, Hampel H, Pearlman R, Jones D, Zhao W, Alsomali M et al (2020) Unexpected expression of mismatch repair protein is more commonly seen with pathogenic missense than with other mutations in Lynch syndrome. Hum Pathol 103:34\u201341. https:\/\/doi.org\/10.1016\/j.humpath.2020.07.001","journal-title":"Hum Pathol"},{"key":"2846_CR8","doi-asserted-by":"publisher","first-page":"vdae102","DOI":"10.1093\/noajnl\/vdae102","volume":"6","author":"A Das","year":"2024","unstructured":"Das A, Ercan AB, Tabori U (2024) An update on central nervous system tumors in germline replication-repair deficiency syndromes. Neurooncol Adv 6:vdae102. https:\/\/doi.org\/10.1093\/noajnl\/vdae102","journal-title":"Neurooncol Adv"},{"key":"2846_CR9","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1158\/2159-8290.CD-23-0559","volume":"14","author":"A Das","year":"2024","unstructured":"Das A, Fernandez NR, Levine A, Bianchi V, Stengs LK, Chung J et al (2024) Combined immunotherapy improves outcome for replication-repair-deficient (RRD) high-grade glioma failing Anti-PD-1 monotherapy: a report from the international RRD consortium. Cancer Discov 14:258\u2013273. https:\/\/doi.org\/10.1158\/2159-8290.CD-23-0559","journal-title":"Cancer Discov"},{"key":"2846_CR10","doi-asserted-by":"publisher","first-page":"4770","DOI":"10.1158\/1078-0432.CCR-23-0411","volume":"29","author":"A Das","year":"2023","unstructured":"Das A, Tabori U, Sambira Nahum LC, Collins NB, Deyell R, Dvir R et al (2023) Efficacy of nivolumab in pediatric cancers with high mutation burden and mismatch repair deficiency. Clin Cancer Res 29:4770\u20134783. https:\/\/doi.org\/10.1158\/1078-0432.CCR-23-0411","journal-title":"Clin Cancer Res"},{"key":"2846_CR11","doi-asserted-by":"publisher","first-page":"2779","DOI":"10.1200\/JCO.20.02636","volume":"39","author":"C Durno","year":"2021","unstructured":"Durno C, Ercan AB, Bianchi V, Edwards M, Aronson M, Galati M et al (2021) Survival benefit for individuals with constitutional mismatch repair deficiency undergoing surveillance. J Clin Oncol 39:2779\u20132790. https:\/\/doi.org\/10.1200\/JCO.20.02636","journal-title":"J Clin Oncol"},{"key":"2846_CR12","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1016\/S1470-2045(24)00026-3","volume":"25","author":"AB Ercan","year":"2024","unstructured":"Ercan AB, Aronson M, Fernandez NR, Chang Y, Levine A, Liu ZA et al (2024) Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an international replication repair deficiency consortium cohort study. Lancet Oncol 25:668\u2013682. https:\/\/doi.org\/10.1016\/S1470-2045(24)00026-3","journal-title":"Lancet Oncol"},{"key":"2846_CR13","doi-asserted-by":"publisher","first-page":"3783","DOI":"10.3390\/cancers14153783","volume":"14","author":"A Favier","year":"2022","unstructured":"Favier A, Varinot J, Uzan C, Duval A, Brocheriou I, Canlorbe G et al (2022) The role of immunohistochemistry markers in endometrial cancer with mismatch repair deficiency: a systematic review. Cancers (Basel) 14:3783. https:\/\/doi.org\/10.3390\/cancers14153783","journal-title":"Cancers (Basel)"},{"key":"2846_CR14","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1007\/s00381-023-06158-x","volume":"40","author":"A Goyal","year":"2024","unstructured":"Goyal A, Rao S, Rishi KS, Ramaswamy V, Sadashiva N, Santosh V (2024) Glioma arising in the setting of mismatch repair deficiency-rare or are we missing it? Childs Nerv Syst 40:233\u2013237. https:\/\/doi.org\/10.1007\/s00381-023-06158-x","journal-title":"Childs Nerv Syst"},{"key":"2846_CR15","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1038\/nature25480","volume":"555","author":"SN Gr\u00f6bner","year":"2018","unstructured":"Gr\u00f6bner SN, Worst BC, Weischenfeldt J, Buchhalter I, Kleinheinz K, Rudneva VA et al (2018) The landscape of genomic alterations across childhood cancers. Nature 555:321\u2013327. https:\/\/doi.org\/10.1038\/nature25480","journal-title":"Nature"},{"key":"2846_CR16","doi-asserted-by":"publisher","first-page":"2342","DOI":"10.1158\/1078-0432.CCR-23-4033","volume":"30","author":"JR Hansford","year":"2024","unstructured":"Hansford JR, Das A, McGee RB, Nakano Y, Brzezinski J, Scollon SR et al (2024) Update on cancer predisposition syndromes and surveillance guidelines for childhood brain tumors. Clin Cancer Res 30:2342\u20132350. https:\/\/doi.org\/10.1158\/1078-0432.CCR-23-4033","journal-title":"Clin Cancer Res"},{"key":"2846_CR17","doi-asserted-by":"publisher","first-page":"1342","DOI":"10.1038\/nm.4191","volume":"22","author":"RJ Hause","year":"2016","unstructured":"Hause RJ, Pritchard CC, Shendure J, Salipante SJ (2016) Classification and characterization of microsatellite instability across 18 cancer types. Nat Med 22:1342\u20131350. https:\/\/doi.org\/10.1038\/nm.4191","journal-title":"Nat Med"},{"key":"2846_CR18","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1038\/s41379-019-0414-6","volume":"33","author":"JF Hechtman","year":"2019","unstructured":"Hechtman JF, Rana S, Middha S, Stadler ZK, Latham A, Benayed R et al (2019) Retained mismatch repair protein expression occurs in approximately 6% of microsatellite instability-high cancers and is associated with missense mutations in mismatch repair genes. Mod Pathol 33:871\u2013879. https:\/\/doi.org\/10.1038\/s41379-019-0414-6","journal-title":"Mod Pathol"},{"key":"2846_CR19","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.jmoldx.2023.10.005","volume":"26","author":"NC Helderman","year":"2024","unstructured":"Helderman NC, Andini KD, van Leerdam ME, van Hest LP, Hoekman DR, Ahadova A et al (2024) MLH1 promotor hypermethylation in colorectal and endometrial carcinomas from patients with lynch syndrome. J Mol Diagn 26:106\u2013114. https:\/\/doi.org\/10.1016\/j.jmoldx.2023.10.005","journal-title":"J Mol Diagn"},{"key":"2846_CR20","unstructured":"International Agency for Research on Cancer (2021) WHO Classification of Tumours Editorial Board. Central nervous system tumours (5th ed.). Lyon, France"},{"key":"2846_CR21","unstructured":"International Agency for Research on Cancer (2023) WHO Classification of Tumours Editorial Board. Genetic Tumour Syndromes (5th ed.). Lyon, France"},{"key":"2846_CR22","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1038\/s41374-021-00694-3","volume":"102","author":"H Kim","year":"2022","unstructured":"Kim H, Lim KY, Park JW, Kang J, Won JK, Lee K et al (2022) Sporadic and Lynch syndrome-associated mismatch repair-deficient brain tumors. Lab Invest 102:160\u2013171. https:\/\/doi.org\/10.1038\/s41374-021-00694-3","journal-title":"Lab Invest"},{"key":"2846_CR23","doi-asserted-by":"publisher","first-page":"4886","DOI":"10.1002\/cncr.33144","volume":"126","author":"SR Kim","year":"2020","unstructured":"Kim SR, Tone A, Kim RH, Cesari M, Clarke BA, Eiriksson L et al (2020) Performance characteristics of screening strategies to identify Lynch syndrome in women with ovarian cancer. Cancer 126:4886\u20134894. https:\/\/doi.org\/10.1002\/cncr.33144","journal-title":"Cancer"},{"key":"2846_CR24","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/S2352-4642(20)30275-3","volume":"5","author":"CP Kratz","year":"2021","unstructured":"Kratz CP, Jongmans MC, Cav\u00e9 H, Wimmer K, Behjati S, Guerrini-Rousseau L et al (2021) Predisposition to cancer in children and adolescents. Lancet Child Adolesc Health 5:142\u2013154. https:\/\/doi.org\/10.1016\/S2352-4642(20)30275-3","journal-title":"Lancet Child Adolesc Health"},{"key":"2846_CR25","doi-asserted-by":"publisher","first-page":"3345","DOI":"10.1158\/0008-5472.CAN-22-0125","volume":"82","author":"SJ Macha","year":"2022","unstructured":"Macha SJ, Koneru B, Burrow TA, Zhu C, Savitski D, Rahman RL et al (2022) Alternative lengthening of telomeres in cancer confers a vulnerability to reactivation of p53 function. Cancer Res 82:3345\u20133358. https:\/\/doi.org\/10.1158\/0008-5472.CAN-22-0125","journal-title":"Cancer Res"},{"key":"2846_CR26","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1007\/s11060-022-04079-4","volume":"159","author":"M Massimino","year":"2022","unstructured":"Massimino M, Vennarini S, Barretta F, Colombo F, Antonelli M, Pollo B et al (2022) How ten-years of reirradiation for paediatric high-grade glioma may shed light on first line treatment. J Neurooncol 159:437\u2013445. https:\/\/doi.org\/10.1007\/s11060-022-04079-4","journal-title":"J Neurooncol"},{"key":"2846_CR27","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1056\/NEJMoa2304194","volume":"389","author":"IK Mellinghoff","year":"2023","unstructured":"Mellinghoff IK, van den Bent MJ, Blumenthal DT, Touat M, Peters KB, Clarke J et al (2023) Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. N Engl J Med 389:589\u2013601. https:\/\/doi.org\/10.1056\/NEJMoa2304194","journal-title":"N Engl J Med"},{"key":"2846_CR28","doi-asserted-by":"publisher","first-page":"368","DOI":"10.2353\/jmoldx.2007.060167","volume":"9","author":"T Mikeska","year":"2007","unstructured":"Mikeska T, Bock C, El-Maarri O, H\u00fcbner A, Ehrentraut D, Schramm J et al (2007) Optimization of quantitative MGMT promoter methylation analysis using pyrosequencing and combined bisulfite restriction analysis. J Mol Diagn 9:368\u2013381. https:\/\/doi.org\/10.2353\/jmoldx.2007.060167","journal-title":"J Mol Diagn"},{"key":"2846_CR29","doi-asserted-by":"publisher","first-page":"3098","DOI":"10.1158\/0008-5472.CAN-09-3290","volume":"70","author":"T Nagasaka","year":"2010","unstructured":"Nagasaka T, Rhees J, Kloor M, Gebert J, Naomoto Y, Boland CR et al (2010) Somatic hypermethylation of MSH2 is a frequent event in Lynch Syndrome colorectal cancers. Cancer Res 70:3098\u20133108. https:\/\/doi.org\/10.1158\/0008-5472.CAN-09-3290","journal-title":"Cancer Res"},{"key":"2846_CR30","doi-asserted-by":"publisher","first-page":"1767","DOI":"10.3748\/wjg.v13.i12.1767","volume":"13","author":"Y Niv","year":"2007","unstructured":"Niv Y (2007) Microsatellite instability and MLH1 promoter hypermethylation in colorectal cancer. World J Gastroenterol 13:1767\u20131769. https:\/\/doi.org\/10.3748\/wjg.v13.i12.1767","journal-title":"World J Gastroenterol"},{"key":"2846_CR31","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1200\/JCO.2017.76.9901","volume":"36","author":"MJ Overman","year":"2018","unstructured":"Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M et al (2018) Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient\/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 36:773\u2013779. https:\/\/doi.org\/10.1200\/JCO.2017.76.9901","journal-title":"J Clin Oncol"},{"key":"2846_CR32","doi-asserted-by":"publisher","DOI":"10.1200\/PO.23.00332","volume":"8","author":"E Papadopoulou","year":"2024","unstructured":"Papadopoulou E, Rigas G, Fountzilas E, Boutis A, Giassas S, Mitsimponas N et al (2024) Microsatellite instability is insufficiently used as a biomarker for lynch syndrome testing in clinical practice. JCO Precis Oncol 8:e2300332. https:\/\/doi.org\/10.1200\/PO.23.00332","journal-title":"JCO Precis Oncol"},{"key":"2846_CR33","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1007\/s40291-020-00462-x","volume":"24","author":"V Pestinger","year":"2020","unstructured":"Pestinger V, Smith M, Sillo T, Findlay JM, Laes JF, Martin G et al (2020) Use of an integrated pan-cancer oncology enrichment next-generation sequencing assay to measure tumour mutational burden and detect clinically actionable variants. Mol Diagn Ther 24:339\u2013349. https:\/\/doi.org\/10.1007\/s40291-020-00462-x","journal-title":"Mol Diagn Ther"},{"key":"2846_CR34","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1093\/jnci\/djaa069","volume":"113","author":"M Pi\u00f1eros","year":"2021","unstructured":"Pi\u00f1eros M, Mery L, Soerjomataram I, Bray F, Steliarova-Foucher E (2021) Scaling up the surveillance of childhood cancer: A global roadmap. J Natl Cancer Inst 113:9\u201315. https:\/\/doi.org\/10.1093\/jnci\/djaa069","journal-title":"J Natl Cancer Inst"},{"key":"2846_CR35","doi-asserted-by":"publisher","first-page":"1147591","DOI":"10.3389\/fonc.2023.1147591","volume":"13","author":"M Rasmussen","year":"2023","unstructured":"Rasmussen M, Sowter P, Gallon R, Durhuus JA, Hayes C, Andersen O et al (2023) Mismatch repair deficiency testing in Lynch syndrome-associated urothelial tumors. Front Oncol 13:1147591. https:\/\/doi.org\/10.3389\/fonc.2023.1147591","journal-title":"Front Oncol"},{"key":"2846_CR36","doi-asserted-by":"publisher","first-page":"757","DOI":"10.3390\/curroncol28010074","volume":"28","author":"R Rittberg","year":"2021","unstructured":"Rittberg R, Harlos C, Rothenmund H, Das A, Tabori U, Sinha N et al (2021) Immune checkpoint inhibition as primary adjuvant therapy for an IDH1-mutant anaplastic astrocytoma in a patient with CMMRD: a case report-usage of immune checkpoint inhibition in CMMRD. Curr Oncol 28:757\u2013766. https:\/\/doi.org\/10.3390\/curroncol28010074","journal-title":"Curr Oncol"},{"key":"2846_CR37","doi-asserted-by":"publisher","first-page":"293","DOI":"10.2353\/jmoldx.2008.080031","volume":"10","author":"J Shia","year":"2008","unstructured":"Shia J (2008) Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part I. The utility of immunohistochemistry. J Mol Diagn 10:293\u2013300. https:\/\/doi.org\/10.2353\/jmoldx.2008.080031","journal-title":"J Mol Diagn"},{"key":"2846_CR38","doi-asserted-by":"publisher","first-page":"1558","DOI":"10.1093\/annonc\/mdz233","volume":"30","author":"N Stjepanovic","year":"2019","unstructured":"Stjepanovic N, Moreira L, Carneiro F, Balaguer F, Cervantes A, Balma\u00f1a J et al (2019) Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 30:1558\u20131571. https:\/\/doi.org\/10.1093\/annonc\/mdz233","journal-title":"Ann Oncol"},{"key":"2846_CR39","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1093\/neuonc\/noac278","volume":"25","author":"JL Stundon","year":"2023","unstructured":"Stundon JL, Ijaz H, Gaonkar KS, Kaufman RS, Jin R, Karras A et al (2023) Alternative lengthening of telomeres (ALT) in pediatric high-grade gliomas can occur without ATRX mutation and is enriched in patients with pathogenic germline mismatch repair (MMR) variants. Neuro Oncol 25:1331\u20131342. https:\/\/doi.org\/10.1093\/neuonc\/noac278","journal-title":"Neuro Oncol"},{"key":"2846_CR40","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1038\/s41591-023-02255-1","volume":"29","author":"D Sturm","year":"2023","unstructured":"Sturm D, Capper D, Andreiuolo F, Gessi M, K\u00f6lsche C, Reinhardt A et al (2023) Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology. Nat Med 29:917\u2013926. https:\/\/doi.org\/10.1038\/s41591-023-02255-1","journal-title":"Nat Med"},{"key":"2846_CR41","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/s00401-020-02243-6","volume":"141","author":"AK Suwala","year":"2021","unstructured":"Suwala AK, Stichel D, Schrimpf D, Kloor M, Wefers AK, Reinhardt A et al (2021) Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis. Acta Neuropathol 141:85\u2013100. https:\/\/doi.org\/10.1007\/s00401-020-02243-6","journal-title":"Acta Neuropathol"},{"key":"2846_CR42","doi-asserted-by":"publisher","first-page":"e32","DOI":"10.1158\/1078-0432.CCR-17-0574","volume":"23","author":"U Tabori","year":"2017","unstructured":"Tabori U, Hansford JR, Achatz MI, Kratz CP, Plon SE, Frebourg T et al (2017) Clinical management and tumor surveillance recommendations of inherited mismatch repair deficiency in childhood. Clin Cancer Res 23:e32\u2013e37. https:\/\/doi.org\/10.1158\/1078-0432.CCR-17-0574","journal-title":"Clin Cancer Res"},{"key":"2846_CR43","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1093\/jnci\/djh034","volume":"96","author":"A Umar","year":"2004","unstructured":"Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, R\u00fcschoff J et al (2004) Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261\u2013268. https:\/\/doi.org\/10.1093\/jnci\/djh034","journal-title":"J Natl Cancer Inst"},{"key":"2846_CR44","doi-asserted-by":"publisher","first-page":"2764","DOI":"10.1158\/2159-8290.CD-21-0094","volume":"11","author":"CM van Tilburg","year":"2021","unstructured":"van Tilburg CM, Pfaff E, Pajtler KW, Langenberg KPS, Fiesel P, Jones BC et al (2021) The pediatric precision oncology INFORM registry: clinical outcome and benefit for patients with very high-evidence targets. Cancer Discov 11:2764\u20132779. https:\/\/doi.org\/10.1158\/2159-8290.CD-21-0094","journal-title":"Cancer Discov"},{"key":"2846_CR45","doi-asserted-by":"publisher","first-page":"1515","DOI":"10.1038\/s41379-022-01109-4","volume":"35","author":"C Wang","year":"2022","unstructured":"Wang C, Zhang L, Vakiani E, Shia J (2022) Detecting mismatch repair deficiency in solid neoplasms: immunohistochemistry, microsatellite instability, or both? Mod Pathol 35:1515\u20131528. https:\/\/doi.org\/10.1038\/s41379-022-01109-4","journal-title":"Mod Pathol"},{"key":"2846_CR46","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1136\/jmedgenet-2014-102284","volume":"51","author":"K Wimmer","year":"2014","unstructured":"Wimmer K, Kratz CP, Vasen HFA, Caron O, Colas C, Entz-Werle N et al (2014) Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium \u201ccare for CMMRD\u201d (C4CMMRD). J Med Genet 51:355\u2013365. https:\/\/doi.org\/10.1136\/jmedgenet-2014-102284","journal-title":"J Med Genet"},{"key":"2846_CR47","doi-asserted-by":"publisher","first-page":"2336","DOI":"10.1056\/NEJMoa1508054","volume":"373","author":"J Zhang","year":"2015","unstructured":"Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J et al (2015) Germline mutations in predisposition genes in pediatric cancer. N Engl J Med 373:2336\u20132346. https:\/\/doi.org\/10.1056\/NEJMoa1508054","journal-title":"N Engl J Med"}],"container-title":["Acta Neuropathologica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-025-02846-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00401-025-02846-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-025-02846-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,2]],"date-time":"2025-02-02T19:23:32Z","timestamp":1738524212000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00401-025-02846-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,2]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["2846"],"URL":"https:\/\/doi.org\/10.1007\/s00401-025-02846-x","relation":{},"ISSN":["1432-0533"],"issn-type":[{"value":"1432-0533","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,2]]},"assertion":[{"value":"13 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 January 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 January 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 February 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"U.H. received advisory board and speaker honoraria from Medac and Bayer, and advisory board honoraria from Servier and Oncomagnetx. All other authors declare no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The HIT-HGG-2013 trial (NCT03243461) was approved by the Ethics Committee of the University Medical Center G\u00f6ttingen, G\u00f6ttingen, Germany (222\/23-EP). The INFORM (S-502\/2013) and MNP2.0 (S-320\/2014) studies were approved by the Ethics Committee of the Medical Faculty Heidelberg, Heidelberg, Germany. Each participant or each participant's guardian gave written informed consent for participation in the respective trial.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"11"}}