Heterogeneous EGFR, CDK4, MDM4, and PDGFRA Gene Expression Profiles in Primary GBM: No Association with Patient Survival

Abstract

Background: The prognostic impact of the expression profile of genes recurrently amplified in glioblastoma multiforme (GBM) remains controversial. Methods: We investigated the RNA gene expression profile of epidermal growth factor receptor (EGFR), cyclin-dependent kinase 4 (CDK4), murine doble minute 4 (MDM4), and platelet derived growth factor receptor alpha (PDGFRA) in 83 primary GBM tumors vs. 42 normal brain tissue samples. Interphase FISH (iFISH) analysis for the four genes, together with analysis of intragenic deletions in EGFR and PDGFRA, were evaluated in parallel at the DNA level. As validation cohort, publicly available RNA gene expression data on 293 samples from 10 different GBM patient series were also studied. Results: At the RNA level, CDK4 was the most frequently overexpressed gene (90%) followed by EGFR (58%) and PDGFRA (58%). Chromosome 7 copy number alterations, i.e., trisomy (49%) and polysomy (44%), showed no clear association with EGFR gene expression levels. In turn, intragenic EGFR deletions were found in 39 patients (47%), including EGFRvIII (46%) in association with EGFRvIVa (4%), EGFRvII (2%) or other EGFR deletions (3%) and PDGFRA deletion of exons 8–9 was found in only two tumors (2%). Conclusions: Overall, none of the gene expression profiles and/or intragenic EGFR deletions showed a significant impact on overall survival of GBM supporting the notion that other still unraveled features of the disease might play a more relevant prognostic role in GBM.

Targeting MDMX for Cancer Therapy: Rationale, Strategies, and Challenges

“…They have found that the malignant gliomas harboring MDMX amplification and overexpression have neither p53 mutation nor MDM2 amplification, supporting the role of MDMX in helping gliomas escape from p53-dependent growth control ( 57 , 58 ). Similar results have been obtained in other studies ( 59 , 60 ). However, no association has been found between the aberrant expression of MDMX and the survival of patients with glioblastoma ( 60 ).…”

“…Similar results have been obtained in other studies ( 59 , 60 ). However, no association has been found between the aberrant expression of MDMX and the survival of patients with glioblastoma ( 60 ). Danovi et al have further shown that MDMX is overexpressed in breast (19%), lung (18%), and colon (19%) cancer and MDMX amplification (5%) is responsible for MDMX overexpression in breast cancer ( 61 ).…”

Tumor cell and immune cell profiles in primary human glioblastoma: Impact on patient outcome

“…Similar to CD133 and SOX2, variable percentages of tumor cells were also found to express other growth factor receptors (EGFR) and adhesion molecules (CD24, CD44) which are known to be positive in GBM tumor cells (44). These results further emphasize the existence of a highly heterogeneous tumor cell hierarchy in GBM with a clear association between specific genetic alterations and protein expression profiles (45), as confirmed here for the EGFR protein expression levels and the EGFR gene status. Despite this, no clear association between the protein expression profiles of GBM tumor cells for the different markers investigated here and neither patient features at diagnosis nor the patient outcome was observed (data not shown).…”

“…EGFR has long been known to be altered in most GBM patients, and to play a key role in the oncogenesis and clinical behavior of GBM (62,63). In this regard, a high percentage of chromosome 7 copy number alterations, (i.e., trisomy and polysomy associated or not with the amplification of the EGFR gene) have also been previously described in GBM in the literature, in which the percentage of EGFR gene amplification ranges from 30% to 70% of all tumors depending on the techniques used, at the same time numerical alterations of chromosome 7 would occur in up to 90% of EGFR non-amplified cases (45,64), in line with our results. Despite this, few studies have investigated the potential relationship between EGFR gene alterations and the immune profile in GBM.…”

Adenosinergic Pathway: A Hope in the Immunotherapy of Glioblastoma

“…The EGFR variants, especially EGFR class III variant (EGFRvIII), are overexpressed in a considerable part of GBM patients, making them an ideal target for immunotherapy [ 69 ]. However, the association of EGFR overexpression and mutations with the overall survival of patients is still controversial [ 70 ]. Moreover, the results of trials showed EGFRvIII downregulation following targeted therapy against EGFRvIII [ 35 , 71 ].…”