Basic and Translational Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, via Gattamelata, 64, 35128, Padova, Italy.
Unit of Genetics and Epigenetic of Pediatric Cancer, Oncohaematology Department, IRCCS Ospedale Pediatrico Bambino Gesù, Viale di San Paolo 15, 00146, Rome, Italy.
J Neurooncol. 2023 May;163(1):47-59. doi: 10.1007/s11060-023-04287-6. Epub 2023 May 4.
Patient-derived cancer cell lines can be very useful to investigate genetic as well as epigenetic mechanisms of transformation and to test new drugs. In this multi-centric study, we performed genomic and transcriptomic characterization of a large set of patient-derived glioblastoma (GBM) stem-like cells (GSCs).
94 (80 I surgery/14 II surgery) and 53 (42 I surgery/11 II surgery) GSCs lines underwent whole exome and trascriptome analysis, respectively.
Exome sequencing revealed TP53 as the main mutated gene (41/94 samples, 44%), followed by PTEN (33/94, 35%), RB1 (16/94, 17%) and NF1 (15/94, 16%), among other genes associated to brain tumors. One GSC sample bearing a BRAF p.V600E mutation showed sensitivity in vitro to a BRAF inhibitor. Gene Ontology and Reactome analysis uncovered several biological processes mostly associated to gliogenesis and glial cell differentiation, S - adenosylmethionine metabolic process, mismatch repair and methylation. Comparison of I and II surgery samples disclosed a similar distribution of mutated genes, with an overrepresentation of mutations in mismatch repair, cell cycle, p53 and methylation pathways in I surgery samples, and of mutations in receptor tyrosine kinase and MAPK signaling pathways in II surgery samples. Unsupervised hierarchical clustering of RNA-seq data produced 3 clusters characterized by distinctive sets of up-regulated genes and signaling pathways.
The availability of a large set of fully molecularly characterized GCSs represents a valuable public resource to support the advancement of precision oncology for the treatment of GBM.
患者来源的癌细胞系可用于深入研究遗传和表观遗传转化机制，并测试新药。在这项多中心研究中，我们对大量患者来源的胶质母细胞瘤（GBM）干细胞样细胞（GSCs）进行了基因组和转录组特征分析。
94 例（80 例手术/14 例活检）和 53 例（42 例手术/11 例活检）GSCs 分别进行了全外显子组和转录组分析。
外显子组测序显示 TP53 是主要突变基因（41/94 例，44%），其次是 PTEN（33/94 例，35%）、RB1（16/94 例，17%）和 NF1（15/94 例，16%）等与脑肿瘤相关的基因。一例携带 BRAF p.V600E 突变的 GSC 样本对 BRAF 抑制剂表现出体外敏感性。基因本体论和反应通路分析揭示了几个主要与神经发生和胶质细胞分化、S-腺苷甲硫氨酸代谢过程、错配修复和甲基化相关的生物学过程。I 期和 II 期手术样本的基因突变分布相似，I 期手术样本中错配修复、细胞周期、p53 和甲基化通路的基因突变占优势，而 II 期手术样本中受体酪氨酸激酶和 MAPK 信号通路的基因突变占优势。RNA-seq 数据的无监督层次聚类产生了 3 个聚类，其特征是具有独特的上调基因和信号通路集。
大量完全分子特征明确的 GCS 提供了一个有价值的公共资源，可支持胶质母细胞瘤治疗的精准肿瘤学进展。
