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000298422 1001_ $$aFriker, Lea L$$b0
000298422 245__ $$aMSH2, MSH6, MLH1, and PMS2 immunohistochemistry as highly sensitive screening method for DNA mismatch repair deficiency syndromes in pediatric high-grade glioma.
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000298422 520__ $$aPediatric 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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000298422 650_7 $$2Other$$aConstitutional mismatch repair deficiency
000298422 650_7 $$2Other$$aImmunohistochemistry
000298422 650_7 $$2Other$$aLynch syndrome
000298422 650_7 $$2Other$$aPediatric high-grade glioma
000298422 650_7 $$0EC 3.6.1.3$$2NLM Chemicals$$aMismatch Repair Endonuclease PMS2
000298422 650_7 $$0EC 3.6.1.-$$2NLM Chemicals$$aPMS2 protein, human
000298422 650_7 $$0EC 3.6.1.3$$2NLM Chemicals$$aMutL Protein Homolog 1
000298422 650_7 $$0EC 3.6.1.3$$2NLM Chemicals$$aMutS Homolog 2 Protein
000298422 650_7 $$0EC 3.6.1.3$$2NLM Chemicals$$aMSH2 protein, human
000298422 650_7 $$2NLM Chemicals$$aDNA-Binding Proteins
000298422 650_7 $$2NLM Chemicals$$aG-T mismatch-binding protein
000298422 650_7 $$2NLM Chemicals$$aMLH1 protein, human
000298422 650_2 $$2MeSH$$aHumans
000298422 650_2 $$2MeSH$$aMismatch Repair Endonuclease PMS2: genetics
000298422 650_2 $$2MeSH$$aMismatch Repair Endonuclease PMS2: metabolism
000298422 650_2 $$2MeSH$$aMutL Protein Homolog 1: genetics
000298422 650_2 $$2MeSH$$aMutS Homolog 2 Protein: genetics
000298422 650_2 $$2MeSH$$aMutS Homolog 2 Protein: metabolism
000298422 650_2 $$2MeSH$$aFemale
000298422 650_2 $$2MeSH$$aBrain Neoplasms: genetics
000298422 650_2 $$2MeSH$$aBrain Neoplasms: pathology
000298422 650_2 $$2MeSH$$aChild
000298422 650_2 $$2MeSH$$aDNA-Binding Proteins: genetics
000298422 650_2 $$2MeSH$$aDNA-Binding Proteins: metabolism
000298422 650_2 $$2MeSH$$aMale
000298422 650_2 $$2MeSH$$aGlioma: genetics
000298422 650_2 $$2MeSH$$aGlioma: pathology
000298422 650_2 $$2MeSH$$aGlioma: metabolism
000298422 650_2 $$2MeSH$$aImmunohistochemistry: methods
000298422 650_2 $$2MeSH$$aAdolescent
000298422 650_2 $$2MeSH$$aDNA Mismatch Repair: genetics
000298422 650_2 $$2MeSH$$aChild, Preschool
000298422 650_2 $$2MeSH$$aNeoplastic Syndromes, Hereditary: genetics
000298422 650_2 $$2MeSH$$aNeoplastic Syndromes, Hereditary: diagnosis
000298422 650_2 $$2MeSH$$aColorectal Neoplasms, Hereditary Nonpolyposis: genetics
000298422 650_2 $$2MeSH$$aColorectal Neoplasms, Hereditary Nonpolyposis: pathology
000298422 650_2 $$2MeSH$$aColorectal Neoplasms, Hereditary Nonpolyposis: diagnosis
000298422 650_2 $$2MeSH$$aInfant
000298422 650_2 $$2MeSH$$aGerm-Line Mutation: genetics
000298422 650_2 $$2MeSH$$aColorectal Neoplasms
000298422 7001_ $$aPerwein, Thomas$$b1
000298422 7001_ $$aWaha, Andreas$$b2
000298422 7001_ $$aDörner, Evelyn$$b3
000298422 7001_ $$aKlein, Rebecca$$b4
000298422 7001_ $$0P:(DE-He78)261d2b84aded878003e6e35d18113831$$aBlattner-Johnson, Mirjam$$b5$$udkfz
000298422 7001_ $$aLayer, Julian P$$b6
000298422 7001_ $$0P:(DE-He78)a46a5b2a871859c8e2d63d2f8c666807$$aSturm, Dominik$$b7$$udkfz
000298422 7001_ $$aNussbaumer, Gunther$$b8
000298422 7001_ $$aKwiecien, Robert$$b9
000298422 7001_ $$aSpier, Isabel$$b10
000298422 7001_ $$aAretz, Stefan$$b11
000298422 7001_ $$aKerl, Kornelius$$b12
000298422 7001_ $$aHennewig, Ulrike$$b13
000298422 7001_ $$aRohde, Marius$$b14
000298422 7001_ $$aKarow, Axel$$b15
000298422 7001_ $$aBluemcke, Ingmar$$b16
000298422 7001_ $$aSchmitz, Ann Kristin$$b17
000298422 7001_ $$aReinhard, Harald$$b18
000298422 7001_ $$aHernáiz Driever, Pablo$$b19
000298422 7001_ $$aWendt, Susanne$$b20
000298422 7001_ $$aWeiser, Annette$$b21
000298422 7001_ $$aGuerreiro Stücklin, Ana S$$b22
000298422 7001_ $$aGerber, Nicolas U$$b23
000298422 7001_ $$avon Bueren, André O$$b24
000298422 7001_ $$aKhurana, Claudia$$b25
000298422 7001_ $$aJorch, Norbert$$b26
000298422 7001_ $$aWiese, Maria$$b27
000298422 7001_ $$aKratz, Christian P$$b28
000298422 7001_ $$aEyrich, Matthias$$b29
000298422 7001_ $$aKarremann, Michael$$b30
000298422 7001_ $$aHerrlinger, Ulrich$$b31
000298422 7001_ $$aHölzel, Michael$$b32
000298422 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David T W$$b33$$udkfz
000298422 7001_ $$aHoffmann, Marion$$b34
000298422 7001_ $$aPietsch, Torsten$$b35
000298422 7001_ $$aGielen, Gerrit H$$b36
000298422 7001_ $$aKramm, Christof M$$b37
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