Histologically distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity
Histologically distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity
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DOI：
10.1007/s00401-015-1493-1
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发表时间：
2016-01-01
影响因子：
12.7
通讯作者：
Jones, David T. W.
中科院分区：
文献类型：
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作者：
Korshunov, Andrey;Capper, David;Jones, David T. W.
与组蛋白 H3 K27 突变的高级神经胶质瘤的相对形态均匀性相反，H3 G34 突变的肿瘤表现为组织病理学异质性肿瘤组，具有胶质母细胞瘤 (GBM) 或中枢神经系统原始神经外胚层肿瘤 (CNS-PNET) 的典型微观特征。在当前的研究中，我们对 81 个 G34 突变中枢神经系统肿瘤进行了综合临床、组织病理学和分子分析。研究常规制备的肿瘤组织的基因组和表观基因组改变。尽管具有不同的组织病理学表现，但具有 H3.3 G34 突变的中枢神经系统肿瘤表现出一致的表观遗传特征，表明其具有单一的生物学起源。与其他 GBM 亚型的比较细胞遗传学分析揭示了 G34 突变肿瘤中 3q 和 4q 缺失的高频率和高特异性。 PDGFRA 扩增在 GBM 病例中比 PNET 形态病例中更常见（分别为 36% 和 5%），而 CCND2 扩增则显示出相反的趋势（5% 和 27%）。生存分析显示，存在扩增的癌基因和 MGMT 甲基化，分别作为不良和良好结果的独立预后标志物。形态变异（GBM 与 PNET）之间没有发现结果差异。因此，G34 突变中枢神经系统肿瘤的不同组织学变异可能包含单一生物实体（具有 H3 G34 突变的高级神经胶质瘤，HGG_G34），应在未来的诊断和治疗分类中概述。因此，应建议筛查 H3.3 G34 突变作为广泛组织学谱上幕上 CNS 肿瘤的常规诊断标志物。
In contrast to the relative morphological uniformity of histone H3 K27-mutant high-grade gliomas, H3 G34-mutant tumors present as a histopathologically heterogeneous group of neoplasms, with microscopic characteristics typical of either glioblastoma (GBM) or central nervous system primitive neuroectodermal tumors (CNS-PNET). In the current study, we performed an integrative clinical, histopathological and molecular analysis of 81 G34-mutant CNS tumors. Routinely prepared tumor tissues were investigated for genomic and epigenomic alterations. Despite their divergent histopathological appearance, CNS tumors with H3.3 G34 mutations displayed uniform epigenetic signatures, suggesting a single biological origin. Comparative cytogenetic analysis with other GBM subtypes disclosed a high frequency and high specificity of 3q and 4q loss across G34-mutant tumors. PDGFRA amplification was more common in cases with GBM than with PNET morphology (36 vs. 5 %, respectively), while CCND2 amplifications showed the opposite trend (5 vs. 27 %). Survival analysis revealed the presence of amplified oncogene(s) and MGMT methylation as independent prognostic markers for poor and favorable outcomes, respectively. No difference in outcome was found between morphological variants (GBM vs. PNET). Thus, different histological variants of G34-mutant CNS tumors likely comprise a single biological entity (high-grade glioma with H3 G34 mutation, HGG_G34), which should be outlined in future diagnostic and therapeutic classifications. Screening for H3.3 G34 mutation should therefore be recommended as a routine diagnostic marker for supratentorial CNS tumors across a broad histological spectrum.