癌症驱动基因的共表达：IDH 野生型胶质母细胞瘤衍生的肿瘤球。

Co-expression of cancer driver genes: IDH-wildtype glioblastoma-derived tumorspheres.

机构信息

Department of Biochemistry and Molecular Biology, College of Medicine, Yonsei University, Seoul, Korea.

Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.

出版信息

J Transl Med. 2020 Dec 14;18(1):482. doi: 10.1186/s12967-020-02647-8.

DOI:10.1186/s12967-020-02647-8

PMID:33317554

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7734785/

Abstract

BACKGROUND

Driver genes of GBM may be crucial for the onset of isocitrate dehydrogenase (IDH)-wildtype (WT) glioblastoma (GBM). However, it is still unknown whether the genes are expressed in the identical cluster of cells. Here, we have examined the gene expression patterns of GBM tissues and patient-derived tumorspheres (TSs) and aimed to find a progression-related gene.

METHODS

We retrospectively collected primary IDH-WT GBM tissue samples (n = 58) and tumor-free cortical tissue samples (control, n = 20). TSs are isolated from the IDH-WT GBM tissue with B27 neurobasal medium. Associations among the driver genes were explored in the bulk tissue, bulk cell, and a single cell RNAsequencing techniques (scRNAseq) considering the alteration status of TP53, PTEN, EGFR, and TERT promoter as well as MGMT promoter methylation. Transcriptomic perturbation by temozolomide (TMZ) was examined in the two TSs.

RESULTS

We comprehensively compared the gene expression of the known driver genes as well as MGMT, PTPRZ1, or IDH1. Bulk RNAseq databases of the primary GBM tissue revealed a significant association between TERT and TP53 (p < 0.001, R = 0.28) and its association increased in the recurrent tumor (p < 0.001, R = 0.86). TSs reflected the tissue-level patterns of association between the two genes (p < 0.01, R = 0.59, n = 20). A scRNAseq data of a TS revealed the TERT and TP53 expressing cells are in a same single cell cluster. The driver-enriched cluster dominantly expressed the glioma-associated long noncoding RNAs. Most of the driver-associated genes were downregulated after TMZ except IGFBP5.

CONCLUSIONS

GBM tissue level expression patterns of EGFR, TERT, PTEN, IDH1, PTPRZ1, and MGMT are observed in the GBM TSs. The driver gene-associated cluster of the GBM single cells were enriched with the glioma-associated long noncoding RNAs.

摘要

背景

胶质母细胞瘤（GBM）的驱动基因可能对异柠檬酸脱氢酶（IDH）野生型（WT）胶质母细胞瘤的发生起关键作用。然而，目前尚不清楚这些基因是否在同一簇细胞中表达。在这里，我们研究了 GBM 组织和患者来源的肿瘤球（TSs）的基因表达模式，旨在寻找一个与进展相关的基因。

方法

我们回顾性收集了 58 例 IDH-WT GBM 组织样本（病例组）和 20 例无肿瘤皮质组织样本（对照组）。TSs 是从 IDH-WT GBM 组织中用 B27 神经基底培养基分离出来的。考虑到 TP53、PTEN、EGFR 和 TERT 启动子的改变状态以及 MGMT 启动子甲基化，我们在批量组织、批量细胞和单细胞 RNA 测序技术（scRNAseq）中探索了驱动基因之间的关联。我们还在两个 TSs 中检查了替莫唑胺（TMZ）对转录组的影响。

结果

我们全面比较了已知驱动基因以及 MGMT、PTPRZ1 或 IDH1 的基因表达。原发性 GBM 组织的批量 RNAseq 数据库显示，TERT 与 TP53 之间存在显著相关性（p<0.001，R=0.28），并且这种相关性在复发性肿瘤中增加（p<0.001，R=0.86）。TSs 反映了组织水平上这两个基因之间的关联模式（p<0.01，R=0.59，n=20）。一个 TS 的 scRNAseq 数据显示，TERT 和 TP53 表达的细胞位于同一个单细胞簇中。富含驱动基因的簇主要表达与神经胶质瘤相关的长非编码 RNA。除 IGFBP5 外，大多数与驱动基因相关的基因在 TMZ 处理后表达下调。