INCLIVA Research Institute, Av. Blasco Ibáñez, 17, 46010 Valencia, Spain.
INCLIVA Research Institute, Av. Blasco Ibáñez, 17, 46010 Valencia, Spain; Department of Pathology, Universitat de València, Av. Blasco Ibáñez, 15, 46010 Valencia, Spain.
Neoplasia. 2020 Jan;22(1):10-21. doi: 10.1016/j.neo.2019.09.001. Epub 2019 Nov 18.
Glioblastoma (GBM) is the most common malignant primary tumor of the central nervous system. With no effective therapy, the prognosis for patients is terrible poor. It is highly heterogeneous and EGFR amplification is its most frequent molecular alteration. In this light, we aimed to examine the genetic heterogeneity of GBM and to correlate it with the clinical characteristics of the patients. For that purpose, we analyzed the status of EGFR and the somatic copy number alterations (CNAs) of a set of tumor suppressor genes and oncogenes. Thus, we found GBMs with high level of EGFR amplification, low level and with no EGFR amplification. Highly amplified tumors showed histological features of aggressiveness. Interestingly, accumulation of CNAs, as a measure of tumor mutational burden, was frequent and significantly associated to shortened survival. EGFR-amplified GBMs displayed both a higher number of concrete CNAs and a higher global tumor mutational burden than their no EGFR-amplified counterparts. In addition to genetic changes previously described in GBM, we found PARK2 and LARGE1 CNAs associated to EGFR amplification. The set of genes analyzed allowed us to explore relevant signaling pathways on GBM. Both PARK2 and LARGE1 are related to receptor tyrosine kinase/PI3K/PTEN/AKT/mTOR-signaling pathway. Finally, we found an association between the molecular pathways altered, EGFR amplification and a poor outcome. Our results underline the potential interest of categorizing GBM according to their EGFR amplification level and the usefulness of assessing the tumor mutational burden. These approaches would open new knowledge possibilities related to GBM biology and therapy.
胶质母细胞瘤（GBM）是中枢神经系统最常见的恶性原发性肿瘤。由于缺乏有效的治疗方法，患者的预后极差。它具有高度异质性，EGFR 扩增是其最常见的分子改变。鉴于此，我们旨在研究 GBM 的遗传异质性，并将其与患者的临床特征相关联。为此，我们分析了一组肿瘤抑制基因和癌基因的 EGFR 状态和体细胞拷贝数改变（CNAs）。因此，我们发现了 EGFR 高扩增、低扩增和无 EGFR 扩增的 GBM。高度扩增的肿瘤表现出侵袭性的组织学特征。有趣的是，作为肿瘤突变负担的衡量标准，CNAs 的积累频繁且与缩短的生存时间显著相关。与无 EGFR 扩增的 GBM 相比，EGFR 扩增的 GBM 显示出更高数量的具体 CNA 和更高的全局肿瘤突变负担。除了先前在 GBM 中描述的遗传变化外，我们还发现 PARK2 和 LARGE1 的 CNA 与 EGFR 扩增相关。分析的基因集使我们能够探索 GBM 中相关的信号通路。PARK2 和 LARGE1 都与受体酪氨酸激酶/PI3K/PTEN/AKT/mTOR 信号通路有关。最后，我们发现分子途径的改变、EGFR 扩增与不良预后之间存在关联。我们的结果强调了根据 EGFR 扩增水平对 GBM 进行分类的潜在意义，以及评估肿瘤突变负担的有用性。这些方法将为 GBM 生物学和治疗开辟新的知识可能性。
