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

被引：0

作者：

Friker, Lea L. ^{[1
,2
]}

Perwein, Thomas ^{[3
,4
]}

Waha, Andreas ^{[1
]}

Doerner, Evelyn ^{[1
]}

Klein, Rebecca ^{[1
]}

Blattner-Johnson, Mirjam ^{[5
,6
,7
]}

Layer, Julian P. ^{[2
,8
]}

Sturm, Dominik ^{[5
,6
,7
,9
]}

Nussbaumer, Gunther ^{[3
]}

Kwiecien, Robert ^{[10
]}

Spier, Isabel ^{[11
]}

Aretz, Stefan ^{[11
]}

Kerl, Kornelius ^{[12
]}

Hennewig, Ulrike ^{[13
]}

Rohde, Marius ^{[13
]}

Karow, Axel ^{[14
,15
]}

Bluemcke, Ingmar ^{[16
]}

Schmitz, Ann Kristin ^{[17
]}

Reinhard, Harald ^{[17
]}

Hernaiz Driever, Pablo ^{[18
,19
,20
,21
]}

Wendt, Susanne ^{[22
]}

Weiser, Annette ^{[23
,24
]}

Guerreiro Stucklin, Ana S.

Gerber, Nicolas U. ^{[23
]}

von Bueren, Andre O. ^{[25
,26
]}

Khurana, Claudia ^{[27
]}

Jorch, Norbert ^{[27
]}

Wiese, Maria ^{[28
]}

Kratz, Christian P. ^{[29
]}

Eyrich, Matthias ^{[30
]}

Karremann, Michael ^{[31
,32
]}

Herrlinger, Ulrich ^{[33
]}

Hoelzel, Michael ^{[2
]}

Jones, David T. W. ^{[5
,6
,7
]}

Hoffmann, Marion ^{[28
]}

Pietsch, Torsten ^{[1
]}

Gielen, Gerrit H. ^{[1
]}

Kramm, Christof M. ^{[28
]}

机构：

[1] Univ Hosp Bonn, Inst Neuropathol, DGNN Brain Tumor Reference Ctr, Venusberg Campus 1, D-53127 Bonn, Germany

[2] Univ Hosp Bonn, Inst Expt Oncol, Bonn, Germany

[3] Med Univ Graz, Dept Pediat & Adolescent Med, Div Pediat Hematol Oncol, Graz, Austria

[4] Med Univ Graz, Res Unit Canc & Inborn Errors Blood & Immun Childr, Styrian Childrens Canc Res, Graz, Austria

[5] Hopp Childrens Canc Ctr Heidelberg KiTZ, Heidelberg, Germany

[6] German Canc Res Ctr, Div Pediat Glioma Res, Heidelberg, Germany

[7] German Canc Consortium DKTK, Heidelberg, Germany

[8] Univ Hosp Bonn, Dept Radiat Oncol, Bonn, Germany

[9] Univ Heidelberg Hosp, Dept Pediat Oncol Hematol & Immunol, Heidelberg, Germany

[10] Univ Munster, Inst Biostat & Clin Res, Munster, Germany

[11] Univ Bonn, Inst Human Genet, Med Fac, Bonn, Germany

[12] Univ Childrens Hosp Munster, Dept Pediat Hematol Oncol, Munster, Germany

[13] Univ Hosp Giessen & Marburg, Dept Pediat Hematol & Oncol, Giessen, Germany

[14] Univ Hosp Erlangen, Dept Pediat & Adolescent Med, Erlangen, Germany

[15] Comprehens Canc Ctr Erlangen, Erlangen, Germany

[16] Univ Hosp Erlangen, Inst Neuropathol, Erlangen, Germany

[17] Asklepios Kinderklin Sankt Augustin, Dept Pediat, St Augustin, Germany

[18] Charite Univ Med Berlin, Dept Pediat Oncol & Hematol, Berlin, Germany

[19] Free Univ Berlin, Berlin, Germany

[20] Humboldt Univ, Berlin, Germany

[21] German HIT LOGG Registry pLGG Children & Adolescen, Berlin, Germany

[22] Univ Hosp Leipzig, Dept Pediat Oncol Hematol & Hemostaseol, Leipzig, Germany

[23] Univ Childrens Hosp Zurich, Dept Oncol, Zurich, Switzerland

[24] Univ Childrens Hosp Zurich, Childrens Res Ctr, Zurich, Switzerland

[25] Univ Hosp Geneva, Dept Pediat Gynecol & Obstet, Div Pediat Oncol & Hematol, Geneva, Switzerland

[26] Univ Geneva, Dept Pediat Gynecol & Obstet, CANSEARCH Res Lab, Fac Med, Geneva, Switzerland

[27] Univ Hosp Ostwestfalen Lippe, Childrens Ctr Bethel, Dept Pediat Hematol & Oncol, Bielefeld, Germany

[28] Univ Med Ctr Gottingen, Div Pediat Hematol & Oncol, Gottingen, Germany

[29] Hannover Med Sch, Dept Pediat Hematol & Oncol, Hannover, Germany

[30] Univ Hosp Wurzburg, Univ Childrens Hosp, Wurzburg, Germany

[31] Heidelberg Univ, Univ Med Ctr Mannheim, Med Fac Mannheim, Dept Pediat & Adolescent Med, Mannheim, Germany

[32] Heidelberg Univ, Univ Med Ctr Mannheim, Med Fac Mannheim, Mannheim Canc Ctr MCC, Mannheim, Germany

[33] Univ Hosp Bonn, Ctr Neurol & CIO ABCD, Dept Neurooncol, Bonn, Germany

来源：

ACTA NEUROPATHOLOGICA | 2025年 / 149卷 / 01期

关键词：

Pediatric high-grade glioma; Lynch syndrome; Constitutional mismatch repair deficiency; Immunohistochemistry; IMMUNE CHECKPOINT INHIBITION; MICROSATELLITE INSTABILITY; LYNCH-SYNDROME; CANCER; HYPERMETHYLATION; PREDISPOSITION; GUIDELINES; MUTATIONS; EXPRESSION; LANDSCAPE;

D O I：

10.1007/s00401-025-02846-x

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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.

引用

页数：17

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