Friker Lea L, Perwein Thomas, Waha Andreas, Dörner Evelyn, Klein Rebecca, Blattner-Johnson Mirjam, Layer Julian P, Sturm Dominik, Nussbaumer Gunther, Kwiecien Robert, Spier Isabel, Aretz Stefan, Kerl Kornelius, Hennewig Ulrike, Rohde Marius, Karow Axel, Bluemcke Ingmar, Schmitz Ann Kristin, Reinhard Harald, Hernáiz Driever Pablo, Wendt Susanne, Weiser Annette, Guerreiro Stücklin Ana S, Gerber Nicolas U, von Bueren André O, Khurana Claudia, Jorch Norbert, Wiese Maria, Kratz Christian P, Eyrich Matthias, Karremann Michael, Herrlinger Ulrich, Hölzel Michael, Jones David T W, Hoffmann Marion, Pietsch Torsten, Gielen Gerrit H, Kramm Christof M
Institute of Neuropathology, DGNN Brain Tumor Reference Center, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.
Institute of Experimental Oncology, University Hospital Bonn, Bonn, Germany.
Acta Neuropathol. 2025 Feb 2;149(1):11. doi: 10.1007/s00401-025-02846-x.
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.
小儿高级别胶质瘤（pedHGG）可能是由DNA错配修复（MMR）基因MSH2、MSH6、MLH1和PMS2中的致病种系变异导致的癌症易感综合征的首发表现。本研究的目的是对pedHGG患者进行林奇综合征和遗传性MMR缺陷（CMMRD）的通用筛查，因为检测到MMR缺陷（MMRD）可能有助于检查点抑制剂的前期治疗应用，并识别患者家族中的变异携带者。作为HIT-HGG-2013试验方案的一部分，我们前瞻性纳入了155例经中心审查的原发性pedHGG患者进行MMR免疫组织化学（IHC）检测。随后将MMR-IHC结果与HIT-HGG-2013、INFORM和MNP2.0试验中独立收集的种系测序数据（全外显子组测序或泛癌DNA panel二代测序）进行比较。MMR-IHC能够在127/155个肿瘤组织中成功进行。该筛查识别出了所有存在林奇综合征或CMMRD的病例（5.5%）。此外，MMR-IHC还检测到了仅存在体细胞MMR基因改变的病例（2.3%），包括MSH2高甲基化作为一种替代的表观遗传沉默机制。大多数已识别的pedHGG MMRD患者没有MMRD家族史，因此，他们是其家族中的索引患者。MMR-IHC中蛋白表达正常的病例在DNA测序中从未显示出MMRD证据。总之，MMR-IHC是一种经济高效、相对广泛可用且快速的筛查方法，用于pedHGG中种系MMRD的检测，具有高敏感性（100%）和特异性（96%）。鉴于pedHGG患者中先前未检测到的MMRD病例患病率相对较高，我们强烈建议将MMR-IHC纳入常规诊断。
