MSH2, MSH6, MLH1, and PMS2 immunohistochemistry as highly sensitive screening method for DNA mismatch repair deficiency syndromes in pediatric high-grade glioma.

Friker, Lea L; Gielen, Gerrit H; Guerreiro Stücklin, Ana S; Wendt, Susanne; von Bueren, André O; Hoffmann, Marion; Hernáiz Driever, Pablo; Herrlinger, Ulrich; Schmitz, Ann Kristin; Aretz, Stefan; Dörner, Evelyn; Eyrich, Matthias; Gerber, Nicolas U; Waha, Andreas; Pietsch, Torsten; Perwein, Thomas; Karremann, Michael; Bluemcke, Ingmar; Jones, David T W; Nussbaumer, Gunther; Klein, Rebecca; Khurana, Claudia; Karow, Axel; Blattner-Johnson, Mirjam; Wiese, Maria; Kratz, Christian P; Reinhard, Harald; Hölzel, Michael; Jorch, Norbert; Kerl, Kornelius; Layer, Julian P; Hennewig, Ulrike; Weiser, Annette; Sturm, Dominik; Kwiecien, Robert; Rohde, Marius; Spier, Isabel; Kramm, Christof M

doi:10.1007/s00401-025-02846-x

Items
Marc 21

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024	7	_	\|a 10.1007/s00401-025-02846-x \|2 doi
024	7	_	\|a pmid:39894875 \|2 pmid
024	7	_	\|a 0001-6322 \|2 ISSN
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037	_	_	\|a DKFZ-2025-00278
041	_	_	\|a English
082	_	_	\|a 610
100	1	_	\|a Friker, Lea L \|b 0
245	_	_	\|a MSH2, MSH6, MLH1, and PMS2 immunohistochemistry as highly sensitive screening method for DNA mismatch repair deficiency syndromes in pediatric high-grade glioma.
260	_	_	\|a Heidelberg \|c 2025 \|b Springer
336	7	_	\|a article \|2 DRIVER
336	7	_	\|a Output Types/Journal article \|2 DataCite
336	7	_	\|a Journal Article \|b journal \|m journal \|0 PUB:(DE-HGF)16 \|s 1738596153_16090 \|2 PUB:(DE-HGF)
336	7	_	\|a ARTICLE \|2 BibTeX
336	7	_	\|a JOURNAL_ARTICLE \|2 ORCID
336	7	_	\|a Journal Article \|0 0 \|2 EndNote
520	_	_	\|a 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 MSH2, MSH6, MLH1, and PMS2. 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' 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 MSH2 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.
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650	_	7	\|a Constitutional mismatch repair deficiency \|2 Other
650	_	7	\|a Immunohistochemistry \|2 Other
650	_	7	\|a Lynch syndrome \|2 Other
650	_	7	\|a Pediatric high-grade glioma \|2 Other
650	_	7	\|a Mismatch Repair Endonuclease PMS2 \|0 EC 3.6.1.3 \|2 NLM Chemicals
650	_	7	\|a PMS2 protein, human \|0 EC 3.6.1.- \|2 NLM Chemicals
650	_	7	\|a MutL Protein Homolog 1 \|0 EC 3.6.1.3 \|2 NLM Chemicals
650	_	7	\|a MutS Homolog 2 Protein \|0 EC 3.6.1.3 \|2 NLM Chemicals
650	_	7	\|a MSH2 protein, human \|0 EC 3.6.1.3 \|2 NLM Chemicals
650	_	7	\|a DNA-Binding Proteins \|2 NLM Chemicals
650	_	7	\|a G-T mismatch-binding protein \|2 NLM Chemicals
650	_	7	\|a MLH1 protein, human \|2 NLM Chemicals
650	_	2	\|a Humans \|2 MeSH
650	_	2	\|a Mismatch Repair Endonuclease PMS2: genetics \|2 MeSH
650	_	2	\|a Mismatch Repair Endonuclease PMS2: metabolism \|2 MeSH
650	_	2	\|a MutL Protein Homolog 1: genetics \|2 MeSH
650	_	2	\|a MutS Homolog 2 Protein: genetics \|2 MeSH
650	_	2	\|a MutS Homolog 2 Protein: metabolism \|2 MeSH
650	_	2	\|a Female \|2 MeSH
650	_	2	\|a Brain Neoplasms: genetics \|2 MeSH
650	_	2	\|a Brain Neoplasms: pathology \|2 MeSH
650	_	2	\|a Child \|2 MeSH
650	_	2	\|a DNA-Binding Proteins: genetics \|2 MeSH
650	_	2	\|a DNA-Binding Proteins: metabolism \|2 MeSH
650	_	2	\|a Male \|2 MeSH
650	_	2	\|a Glioma: genetics \|2 MeSH
650	_	2	\|a Glioma: pathology \|2 MeSH
650	_	2	\|a Glioma: metabolism \|2 MeSH
650	_	2	\|a Immunohistochemistry: methods \|2 MeSH
650	_	2	\|a Adolescent \|2 MeSH
650	_	2	\|a DNA Mismatch Repair: genetics \|2 MeSH
650	_	2	\|a Child, Preschool \|2 MeSH
650	_	2	\|a Neoplastic Syndromes, Hereditary: genetics \|2 MeSH
650	_	2	\|a Neoplastic Syndromes, Hereditary: diagnosis \|2 MeSH
650	_	2	\|a Colorectal Neoplasms, Hereditary Nonpolyposis: genetics \|2 MeSH
650	_	2	\|a Colorectal Neoplasms, Hereditary Nonpolyposis: pathology \|2 MeSH
650	_	2	\|a Colorectal Neoplasms, Hereditary Nonpolyposis: diagnosis \|2 MeSH
650	_	2	\|a Infant \|2 MeSH
650	_	2	\|a Germ-Line Mutation: genetics \|2 MeSH
650	_	2	\|a Colorectal Neoplasms \|2 MeSH
700	1	_	\|a Perwein, Thomas \|b 1
700	1	_	\|a Waha, Andreas \|b 2
700	1	_	\|a Dörner, Evelyn \|b 3
700	1	_	\|a Klein, Rebecca \|b 4
700	1	_	\|a Blattner-Johnson, Mirjam \|0 P:(DE-He78)261d2b84aded878003e6e35d18113831 \|b 5 \|u dkfz
700	1	_	\|a Layer, Julian P \|b 6
700	1	_	\|a Sturm, Dominik \|0 P:(DE-He78)a46a5b2a871859c8e2d63d2f8c666807 \|b 7 \|u dkfz
700	1	_	\|a Nussbaumer, Gunther \|b 8
700	1	_	\|a Kwiecien, Robert \|b 9
700	1	_	\|a Spier, Isabel \|b 10
700	1	_	\|a Aretz, Stefan \|b 11
700	1	_	\|a Kerl, Kornelius \|b 12
700	1	_	\|a Hennewig, Ulrike \|b 13
700	1	_	\|a Rohde, Marius \|b 14
700	1	_	\|a Karow, Axel \|b 15
700	1	_	\|a Bluemcke, Ingmar \|b 16
700	1	_	\|a Schmitz, Ann Kristin \|b 17
700	1	_	\|a Reinhard, Harald \|b 18
700	1	_	\|a Hernáiz Driever, Pablo \|b 19
700	1	_	\|a Wendt, Susanne \|b 20
700	1	_	\|a Weiser, Annette \|b 21
700	1	_	\|a Guerreiro Stücklin, Ana S \|b 22
700	1	_	\|a Gerber, Nicolas U \|b 23
700	1	_	\|a von Bueren, André O \|b 24
700	1	_	\|a Khurana, Claudia \|b 25
700	1	_	\|a Jorch, Norbert \|b 26
700	1	_	\|a Wiese, Maria \|b 27
700	1	_	\|a Kratz, Christian P \|b 28
700	1	_	\|a Eyrich, Matthias \|b 29
700	1	_	\|a Karremann, Michael \|b 30
700	1	_	\|a Herrlinger, Ulrich \|b 31
700	1	_	\|a Hölzel, Michael \|b 32
700	1	_	\|a Jones, David T W \|0 P:(DE-He78)551bb92841f634070997aa168d818492 \|b 33 \|u dkfz
700	1	_	\|a Hoffmann, Marion \|b 34
700	1	_	\|a Pietsch, Torsten \|b 35
700	1	_	\|a Gielen, Gerrit H \|b 36
700	1	_	\|a Kramm, Christof M \|b 37
773	_	_	\|a 10.1007/s00401-025-02846-x \|g Vol. 149, no. 1, p. 11 \|0 PERI:(DE-600)1458410-4 \|n 1 \|p 11 \|t Acta neuropathologica \|v 149 \|y 2025 \|x 0001-6322
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Marc 21

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