Department of Neurosurgery, Huashan Hospital, Fudan University, Wulumuqi Zhong Road 12, Shanghai, 200040, China.
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong, China.
Brain Pathol. 2019 Nov;29(6):782-792. doi: 10.1111/bpa.12720. Epub 2019 Apr 10.
Giant cell glioblastoma (gcGBM) is a rare histological variant of GBM, accounting for about 1% of all GBM. The prognosis is poor generally though gcGBM does slightly better than the other IDH-wild-type GBM. Because of the rarity of the cases, there has been no comprehensive molecular analysis of gcGBM. Previously, single-gene study identified genetic changes in TP53, PTEN and TERT promoter mutation in gcGBM. In this report, we performed whole-exome sequencing (WES) to identify somatically acquired mutations and copy number variations (CNVs) in 10 gcGBM genomes. We also examined TERT promoter mutation and MGMT methylation in our cohort. On top of the reported mutations, WES revealed ATRX, PIK3R1, RB1 and SETD2 as the recurrent mutations in gcGBM. Notably, one tumor harbored a mutation in MutS homolog 6 (MSH6) that is a key mismatch repair (MMR) gene. This tumor demonstrated hypermutation phenotype and showed an increased number of somatic mutations. TERT promoter mutation and MGMT methylation were observed in 20% and 40% of our samples, respectively. In conclusion, we described relevant mutation profiling for developing future targeted therapies in gcGBM.
巨细胞胶质母细胞瘤（gcGBM）是胶质母细胞瘤的一种罕见组织学变体，约占所有胶质母细胞瘤的 1%。尽管 gcGBM 的预后略好于其他 IDH 野生型 GBM，但总体预后仍较差。由于病例罕见，目前还没有对 gcGBM 进行全面的分子分析。先前的单基因研究在 gcGBM 中鉴定了 TP53、PTEN 和 TERT 启动子突变的遗传变化。在本报告中，我们对 10 例 gcGBM 基因组进行了全外显子组测序（WES），以鉴定体细胞获得的突变和拷贝数变异（CNVs）。我们还在我们的队列中检查了 TERT 启动子突变和 MGMT 甲基化。除了已报道的突变外，WES 还揭示了 ATRX、PIK3R1、RB1 和 SETD2 是 gcGBM 中的高频突变基因。值得注意的是，一个肿瘤携带了 MutS 同源物 6（MSH6）的突变，这是一个关键的错配修复（MMR）基因。该肿瘤表现出高度突变表型，并显示出更多的体细胞突变。我们的样本中分别有 20%和 40%观察到 TERT 启动子突变和 MGMT 甲基化。总之，我们描述了 gcGBM 中相关的突变谱，为开发未来的靶向治疗提供了依据。
