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.

中文翻译：

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体细胞拷贝数改变与原发性胶质母细胞瘤患者的EGFR扩增和生存期缩短有关。

胶质母细胞瘤（GBM）是中枢神经系统最常见的恶性原发肿瘤。没有有效的治疗方法，患者的预后很差。它是高度异质的，EGFR扩增是其最常见的分子改变。有鉴于此，我们旨在检查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EGFR的状态以及一组抑癌基因和癌基因的体细胞拷贝数变化（CNA）。因此，我们发现GBM具有高水平的EGFR扩增，低水平且无EGFR扩增。高度扩增的肿瘤表现出侵袭性的组织学特征。有趣的是，CNA的积累是衡量肿瘤突变负担的一种手段，并且经常与生存期缩短相关。EGFR扩增的GBM与非EGFR扩增的GBM相比，显示出更多的具体CNA和更高的整体肿瘤突变负担。除了先前在GBM中描述的遗传变化外，我们还发现了与EGFR扩增相关的PARK2和LARGE1 CNA。分析的基因集使我们能够探索GBM上的相关信号传导途径。PARK2和LARGE1都与受体酪氨酸激酶/ PI3K / PTEN / AKT / mTOR信号通路有关。最后，我们发现分子途径改变，EGFR扩增与不良结局之间存在关联。我们的结果强调了根据GBM的EGFR扩增水平对GBM进行分类的潜在兴趣，以及评估肿瘤突变负担的有用性。这些方法将打开与GBM生物学和治疗有关的新知识的可能性。