Epithelioid glioblastomas stratify into established diagnostic subsets upon integrated molecular analysis
Epithelioid glioblastomas stratify into established diagnostic subsets upon integrated molecular analysis
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DOI：
10.1111/bpa.12566
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发表时间：
2018-09-01
期刊：
影响因子：
6.4
通讯作者：
von Deimling, Andreas
中科院分区：
文献类型：
--
作者：
Korshunov, Andrey;Chavez, Lukas;von Deimling, Andreas
上皮样胶质母细胞瘤（eGBM）是目前WHO 2016分类中新定义的罕见GBM变体。BRAF V600E突变在这些肿瘤中过度表达，并且已知与间变性上皮样PXA（ePXA）存在一些形态学重叠。为了进一步阐明这一诊断类别，我们对64例最初诊断为eGBM的儿童和成人病例进行了分子特征分析。使用基于阵列的甲基化和BRAF和TERT基因的直接测序来分析肿瘤。我们的研究结果表明，相当大的分子和临床异质性之间的eGBM队列。甲基化模式、拷贝数改变和突变分析数据结合临床发现揭示了三种不同的、明确的肿瘤亚型：（ii）预后不良的IDHwt GBM样肿瘤，主要发生在老年人中，尽管具有更频繁的BRAF突变（17），和（iii）RTK1儿童GBM样肿瘤，在儿童和年轻人中具有中等预后，与染色体断裂和频繁的PDGFRA扩增相关（9）。我们的结论是，组织病理学定义的eGBM不代表一个单一的诊断实体，而是至少三个分子和生物学上不同的类别。因此，建议通过全基因组分子分析进行额外的分子检测，以进一步对这些罕见病例进行分层。
Epithelioid glioblastoma (eGBM) is a newly defined and rare GBM variant in the current WHO 2016 classification. BRAF V600E mutation is overrepresented in these tumors and there is known some morphological overlap with anaplastic epithelioid PXA (ePXA). In order to further elucidate this diagnostic category, we molecularly characterized 64 pediatric and adult examples initially diagnosed as eGBM. Tumors were analyzed using array based methylation and direct sequencing of the BRAF and TERT genes. Our results demonstrated considerable molecular and clinical heterogeneity among eGBM cohort. Methylation patterns, copy number alterations, and mutational analysis data, in combination with clinical findings disclosed three different, well established tumor subtypes: (i) PXA-like tumors with favorable prognosis, predominantly in children and young adults (38), (ii) IDHwt GBM-like tumors with poor prognosis, mainly occurring in older adults, albeit with more frequent BRAF mutations (17), and (iii) RTK1 pediatric GBM-like neoplasms of intermediate prognosis in children and young adults, associated with chromothripsis and frequent PDGFRA amplifications (9). We conclude that the histopathologically defined eGBM do not represent a single diagnostic entity, but rather at least three molecularly and biologically distinct categories. Therefore, additional molecular testing through genome-wide molecular profiling is recommended to further stratify these rare cases.