A subset of gliomas has DNA repair defects that lead to hypermutated genomes. While such tumors are resistant to alkylating chemotherapies, they may also express more mutant neoantigens on their cell surfaces, and thus be more responsive to immunotherapies. A fast, inexpensive method of screening for hypermutated gliomas would therefore be of great clinical value. Since immunohistochemistry (IHC) for the DNA mismatch repair (MMR) proteins Msh2, Msh6, Mlh1, and Pms2 is already used to screen for hypermutated colorectal cancers, we sought to determine whether that panel might have similar utility in gliomas. MMR IHC was scored in 100 WHO grade I-IV gliomas (from 96 patients) with known tumor mutation burden (TMB), while blinded to TMB data. Cases included 70 grade IV GBMs, 13 grade III astrocytomas, 4 grade II astrocytomas (3 diffuse astrocytomas and 1 pleomorphic xanthoastrocytoma), 1 grade I pilocytic astrocytoma, 2 grade III oligodendrogliomas, 7 grade II oligodendrogliomas, and 3 grade I glioneuronal tumors. Eight of 100 tumors showed loss of one or more MMR proteins by IHC, and all 8 were hypermutated. Among the remaining 92 gliomas with intact MMR IHC, only one was hypermutated; that tumor had an inactivating mutation in another DNA repair gene, ATM. Overall accuracy, sensitivity, and specificity for DNA MMR IHC compared to the gold standard of TMB were 99, 89, and 100%, respectively. The strongest correlates with hypermutation were prior TMZ treatment, MGMT promoter methylation, and IDH1 mutation. Among the 8 MMR-deficient hypermutated gliomas, 4 (50%) contained both MMR-lost and MMR-retained tumor cells. Together, these data suggest that MMR IHC could be a viable front-line screening test for gliomas in which immunotherapy is being considered. They also suggest that not all cells in a hypermutated glioma may actually be MMR-deficient, a finding that might need to be considered when treating such tumors with immunotherapies.

中文翻译：

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DNA错配修复酶免疫组织化学作为超突变神经胶质瘤筛查试验的功效。

胶质瘤的子集具有DNA修复缺陷，导致基因组超突变。尽管此类肿瘤对烷基化化学疗法具有抗性，但它们也可能在其细胞表面表达更多的突变新抗原，因此对免疫疗法的反应更强。因此，一种快速，廉价的筛查超突变神经胶质瘤的方法将具有巨大的临床价值。由于用于DNA错配修复（MMR）蛋白Msh2，Msh6，Mlh1和Pms2的免疫组化（IHC）已经用于筛选超突变大肠癌，因此我们试图确定该小组在神经胶质瘤中是否具有相似的用途。在100例已知肿瘤突变负担（TMB）的WHO WHO I-IV胶质瘤（来自96例患者）中对MMR IHC评分，而对TMB数据不了解。病例包括70个IV级GBM，13个III级星形细胞瘤，II级星形细胞瘤4例（弥漫性星形细胞瘤3例，多形性黄体星形细胞瘤1例）I级绒毛状星形细胞瘤1例，III级少突神经胶质瘤2例，II少突神经胶质瘤7例，I级胶质神经胶质瘤3例。100例肿瘤中有8例显示IHC丢失了一种或多种MMR蛋白，所有8例均发生了超突变。在剩下的完整MMR IHC的92例神经胶质瘤中，只有1例发生了突变。该肿瘤在另一个DNA修复基因ATM中具有失活突变。与TMB黄金标准相比，DNA MMR IHC的总体准确性，敏感性和特异性分别为99％，89％和100％。与超变异性最强的相关性是先前的TMZ治疗，MGMT启动子甲基化和IDH1变异。在8个MMR缺陷型高突变神经胶质瘤中，有4个（50％）包含MMR缺失和MMR保留的肿瘤细胞。一起，这些数据表明，MMR IHC可能是正在考虑进行免疫治疗的神经胶质瘤的可行的一线筛查试验。他们还暗示，并非高突变神经胶质瘤中的所有细胞实际上可能都是MMR缺陷的，这一发现在用免疫疗法治疗此类肿瘤时可能需要考虑。