Whole-exome sequencing revealed mutational profiles of giant cell glioblastomas
Whole-exome sequencing revealed mutational profiles of giant cell glioblastomas
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全外显子组测序揭示巨细胞胶质母细胞瘤的突变谱
DOI：
10.1111/bpa.12720
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发表时间：
2019-11-01
期刊：
影响因子：
6.4
通讯作者：
Ng, Ho-Keung
中科院分区：
文献类型：
--
作者：
Shi, Zhi-feng;Li, Kay Ka-Wai;Ng, Ho-Keung
巨细胞胶质母细胞瘤（gcGBM）是GBM的一种罕见的组织学变异型，约占所有GBM的1%。尽管 gcGBM 的预后总体较差，但 gcGBM 的预后略好于其他 IDH 野生型 GBM。由于病例罕见，目前还没有对 gcGBM 进行全面的分子分析。此前，单基因研究鉴定了gcGBM中TP53、PTEN和TERT启动子突变的遗传变化。在本报告中，我们进行了全外显子组测序 (WES)，以识别 10 个 gcGBM 基因组中的体细胞获得性突变和拷贝数变异 (CNV)。我们还检查了队列中的 TERT 启动子突变和 MGMT 甲基化。除了报告的突变之外，WES 还揭示了 ATRX、PIK3R1、RB1 和 SETD2 是 gcGBM 中的复发突变。值得注意的是，一种肿瘤在 MutS 同源物 6 (MSH6) 中存在突变，这是一种关键的错配修复 (MMR) 基因。该肿瘤表现出超突变表型，并显示出体细胞突变数量增加。我们分别在 20% 和 40% 的样本中观察到 TERT 启动子突变和 MGMT 甲基化。总之，我们描述了用于开发未来 gcGBM 靶向治疗的相关突变分析。
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.