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Abstract：
Oligodendrogliomas are defined by mutation in isocitrate dehydrogenase (NADP(+)) (IDH)1/2 genes and chromosome 1p/19q codeletion. World Health Organisation diagnosis endorses testing for 1p/19q codeletion to distinguish IDH mutant (Mut) oligodendrogliomas from astrocytomas because these gliomas require different treatments and they have different outcomes. Several methods have been used to identify 1p/19q status; however, these techniques are not routinely available and require substantial infrastructure investment. Two recent studies reported reduced immunostaining for trimethylation at lysine 27 on histone H3 (H3K27me3) in IDH Mut 1p/19q codeleted oligodendroglioma. However, the specificity of H3K27me3 immunostaining in this setting is controversial. Therefore, we developed an easy-to-implement immunohistochemical surrogate for IDH Mut glioma subclassification and evaluated a validated adult glioma cohort. We screened 145 adult glioma cases, consisting of 45 IDH Mut and 1p/19q codeleted oligodendrogliomas, 30 IDH Mut astrocytomas, 16 IDH wild-type (Wt) astrocytomas, and 54 IDH Wt glioblastomas (GBMs). We compared immunostaining with DNA sequencing and fluorescent in situ hybridization analysis and assessed differences in H3K27me3 staining between oligodendroglial and astrocytic lineages and between IDH1-R132H and non-canonical (non-R132H) IDH1/2 Mut oligodendroglioma. A loss of H3K27me3 was observed in 36/40 (90%) of IDH1-R132H Mut oligodendroglioma. In contrast, loss of H3K27me3 was never seen in IDH1-R132L or IDH2-mutated 1p/19q codeleted oligodendrogliomas. IDH Mut astrocytoma, IDH Wt astrocytoma and GBM showed preserved nuclear staining in 87%, 94%, and 91% of cases, respectively. A high recursive partitioning model predicted probability score (0.9835) indicated that the loss of H3K27me3 is frequent to IDH1-R132H Mut oligodendroglioma. Our results demonstrate H3K27me3 immunohistochemical evaluation to be a cost-effective and reliable method for defining 1p/19q codeletion along with IDH1-R132H and ATRX immunostaining, even in the absence of 1p/19q testing.
摘要：
少突神经胶质瘤由异柠檬酸脱氢酶(NADP(+))(IDH)1/2基因的突变和染色体1p/19q共缺失定义。世界卫生组织的诊断支持对1p/19q共缺失进行测试，以区分IDH突变型（Mut）少突神经胶质瘤与星形细胞瘤，因为这些神经胶质瘤需要不同的治疗方法，并且具有不同的结果。已经使用了几种方法来识别1p/19q状态；然而，这些技术不是常规可用的，需要大量的基础设施投资。最近的两项研究报道了IDHMut1p/19q缺失的少突胶质细胞瘤中组蛋白H3（H3K27me3）上赖氨酸27的三甲基化免疫染色降低。然而,H3K27me3免疫染色在这种情况下的特异性存在争议.因此,我们开发了一种易于实施的IDHMut神经胶质瘤亚分类的免疫组织化学替代方法,并评估了一个经过验证的成人神经胶质瘤队列.我们筛选了145例成人胶质瘤病例，由45个IDHMut和1p/19q共同缺失的少突胶质细胞瘤组成，30IDHMut星形细胞瘤，16IDH野生型（Wt）星形细胞瘤，和54个IDHWt胶质母细胞瘤（GBM）。我们将免疫染色与DNA测序和荧光原位杂交分析进行了比较，并评估了少突胶质细胞和星形胶质细胞谱系之间以及IDH1-R132H与非经典（非R132H）IDH1/2Mut少突胶质细胞瘤之间的H3K27me3染色差异。在IDH1-R132HMut少突胶质细胞瘤的36/40（90％）中观察到H3K27me3的损失。相比之下,在IDH1-R132L或IDH2突变的1p/19q共缺失少突胶质细胞瘤中从未发现H3K27me3缺失。IDHMut星形细胞瘤，IDHWt星形细胞瘤和GBM显示出87％的保留核染色，94%,91%的病例，分别。高递归分区模型预测的概率得分（0.9835）表明，IDH1-R132HMut少突胶质细胞瘤经常丢失H3K27me3。我们的结果表明H3K27me3免疫组织化学评估是一种经济有效且可靠的方法，用于定义1p/19q共缺失以及IDH1-R132H和ATRX免疫染色，即使在没有1p/19q测试的情况下。
