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@ARTICLE{Friker:298422,
      author       = {L. L. Friker and T. Perwein and A. Waha and E. Dörner and
                      R. Klein and M. Blattner-Johnson$^*$ and J. P. Layer and D.
                      Sturm$^*$ and G. Nussbaumer and R. Kwiecien and I. Spier and
                      S. Aretz and K. Kerl and U. Hennewig and M. Rohde and A.
                      Karow and I. Bluemcke and A. K. Schmitz and H. Reinhard and
                      P. Hernáiz Driever and S. Wendt and A. Weiser and A. S.
                      Guerreiro Stücklin and N. U. Gerber and A. O. von Bueren
                      and C. Khurana and N. Jorch and M. Wiese and C. P. Kratz and
                      M. Eyrich and M. Karremann and U. Herrlinger and M. Hölzel
                      and D. T. W. Jones$^*$ and M. Hoffmann and T. Pietsch and G.
                      H. Gielen and C. M. Kramm},
      title        = {{MSH}2, {MSH}6, {MLH}1, and {PMS}2 immunohistochemistry as
                      highly sensitive screening method for {DNA} mismatch repair
                      deficiency syndromes in pediatric high-grade glioma.},
      journal      = {Acta neuropathologica},
      volume       = {149},
      number       = {1},
      issn         = {0001-6322},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2025-00278},
      pages        = {11},
      year         = {2025},
      abstract     = {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.},
      keywords     = {Humans / Mismatch Repair Endonuclease PMS2: genetics /
                      Mismatch Repair Endonuclease PMS2: metabolism / MutL Protein
                      Homolog 1: genetics / MutS Homolog 2 Protein: genetics /
                      MutS Homolog 2 Protein: metabolism / Female / Brain
                      Neoplasms: genetics / Brain Neoplasms: pathology / Child /
                      DNA-Binding Proteins: genetics / DNA-Binding Proteins:
                      metabolism / Male / Glioma: genetics / Glioma: pathology /
                      Glioma: metabolism / Immunohistochemistry: methods /
                      Adolescent / DNA Mismatch Repair: genetics / Child,
                      Preschool / Neoplastic Syndromes, Hereditary: genetics /
                      Neoplastic Syndromes, Hereditary: diagnosis / Colorectal
                      Neoplasms, Hereditary Nonpolyposis: genetics / Colorectal
                      Neoplasms, Hereditary Nonpolyposis: pathology / Colorectal
                      Neoplasms, Hereditary Nonpolyposis: diagnosis / Infant /
                      Germ-Line Mutation: genetics / Colorectal Neoplasms /
                      Constitutional mismatch repair deficiency (Other) /
                      Immunohistochemistry (Other) / Lynch syndrome (Other) /
                      Pediatric high-grade glioma (Other) / Mismatch Repair
                      Endonuclease PMS2 (NLM Chemicals) / PMS2 protein, human (NLM
                      Chemicals) / MutL Protein Homolog 1 (NLM Chemicals) / MutS
                      Homolog 2 Protein (NLM Chemicals) / MSH2 protein, human (NLM
                      Chemicals) / DNA-Binding Proteins (NLM Chemicals) / G-T
                      mismatch-binding protein (NLM Chemicals) / MLH1 protein,
                      human (NLM Chemicals)},
      cin          = {B360 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)B360-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39894875},
      doi          = {10.1007/s00401-025-02846-x},
      url          = {https://inrepo02.dkfz.de/record/298422},
}