Somatic copy number alterations are associated with EGFR amplification and shortened survival in patients with primary glioblastoma

Abstract

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.

Identification of New Genetic Clusters in Glioblastoma Multiforme: EGFR Status and ADD3 Losses Influence Prognosis

“…The point of iFISH remains the possibility of separating that intermediately amplified group, for which it is not entirely clear whether it represents a progression via the amplification status or a separate path for tumor progression in GB. In any case, MLPA proves to be an easy and fast technique, with the additional advantage of being able to determine mutant variants such it is EGFRvIII, in agreement with previous works [21,24,31,35].…”

“…The use of iFISH to precisely determine the EGFR amplification status is the current gold-standard in GB [19,40]. Previous works of our and others groups, demonstrated that this method allows the detection of intermediate levels of amplification [19,24]. Lassman and his colleagues deepened the potential of different new techniques in comparison to iFISH with positive results [40].…”

“…It is also disappointing that while TKI therapies have been successfully expanded to multiple types of cancer, none of them have improved the lifespan of GB patients [18]. Nevertheless, the interest of assessing EGFR copy number status [19][20][21][22][23][24] along with variants that have been related to cell proliferation, angiogenesis and invasion, and thus, with shortened survival, such as the EGFR variant III (EGFRvIII) [25][26][27], is undeniable.…”

“…There is still a long way to progressively introduce objective biomarkers towards precision medicine adapted to the molecular profile of the tumor. High-throughput user-friendly techniques such as multiplex ligation-dependent probe amplification (MLPA) could be optimal for the development of new personalized therapies [24,30].…”

STAT3‑PTTG11 abrogation inhibits proliferation and induces apoptosis in malignant glioma cells

“…In secondary GBM, mutations occur more commonly in the isocitrate dehydrogenase 1 or 2 and TP53 genes (5,6). In ~80% of GBMs, there are also changes in tyrosine kinase activity transmembrane receptor signaling pathways, the p53 pathway (TP53/mouse double minute 2 homolog/p14ARF), the phosphorylated retinoblastoma (RB) pathway [RB1/cyclin-dependant kinase (CDK) inhibitor 2A/CDK4] and the telomerase reverse transcriptase promoter region (pTERT) (7,8). The high variation in the genes involved in GBM is an important reason for the poor efficacy of chemotherapy drugs.…”