In xenograft tumors and molecularly pretyped glioblastomas, the reactivity pattern was as follows: 528 reactive with amplified and nonamplified wtEGFR; DH8.3 reactive with DeltaEGFR; and 806 reactive with amplified/overexpressed wtEGFR (with or without DeltaEGFR).
EGFR was significantly associated with all glioma and glioblastoma in males only and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci.
High serum EGFR and ErbB2 levels were associated with risk of developing glioblastoma (P = 0.008; OR = 1.58, 95 % CI = 1.13-2.22 and P = 0.017, OR = 1.63, 95 % CI = 1.09-2.44, respectively).
Of note, we identified a function for S518-Merlin, which is distinct from what has been reported when the expression of Merlin is diminished in relation to EGFR and NOTCH1 expression, providing first-time evidence that demonstrates that the phosphorylation of S518-Merlin in glioblastoma promotes oncogenic properties that are not only the result of inactivation of the tumor suppressor role of Merlin but also an independent process implicating a Merlin-driven regulation of NOTCH1 and EGFR.
For each of the three cancer types examined, the aberrations in several loci are associated with cancer-type specific biological pathways that have been described in the literature: CNAs of chromosome (chr) 7p13 were significantly correlated with epidermal growth factor receptor signaling pathway in glioblastoma multiforme, chr 13q with NF-kappaB cascades in bladder cancer, and chr 11p with Reck pathway in breast cancer.
Our data support a role of these EGFR polymorphisms in determining glioma susceptibility, with potential relevance for molecularly based stratification of patients with glioblastoma for individualized therapies.
Consistent with previous reports, this method detected EGFRvIII exclusively in EGFR-amplified glioblastomas [8 (44%)], which was confirmed using long-range PCR.
To study the role of EGFRvIII in tumor angiogenesis, we prepared LN229 glioblastoma transfected with enhanced green fluorescent protein (EGFP), wild-type EGFR, or EGFRvIII (LN229-WT or -vIII), and examined tumor growth and microvessel density in the tumors.
These results are consistent with and corroborate our previous findings demonstrating that targeting these two parallel pathways with c-Met and EGFR inhibitor therapy provides substantial anti-tumor activity in glioblastoma models.
In addition, coexpression of phosphatase tensin homolog on chromosome ten (PTEN) and a mutant variant of the epidermal growth factor receptor (EGFRvIII) appears to predict sensitivity of recurrent glioblastomas to EGFR inhibitors.
These receptors are de-regulated in many human tumors, and EGFR amplification, overexpression, and mutations are detected at a high frequency in carcinomas and glioblastomas, which are tumors of epithelial and glial origin, respectively.
Overexpression of EGFR was found to be an indicator of poor prognosis in overall survival in glioma patients (HR =1.72, 95% CI 1.32-2.25, <i>P</i>=0.000, random effect) and glioblastoma multiforme patients (HR =1.57, 95% CI 1.15-2.14, <i>P</i>=0.004, random effect).
Expression of a panel of seven microRNAs (hsa-miR-34a, hsa-miR-16, hsa-miR-17, hsa-miR-21, hsa-miR-221, hsa-miR-326, and hsa-miR-375) and seven target genes ( E2F3, PI3KCA, TOM34, WNT5A, PDCD4, DFFA, and EGFR) in 43 glioblastoma multiforme specimens were profiled compared to non-cancer tissues via quantitative reverse transcription-polymerase chain reaction.
This study combines radiation therapy to prime the tumor for nanoparticle uptake along with the targeting effect of iRGD-conjugated nanoparticles to yield a straightforward but effective approach for combined EGFR inhibition and immunotherapy against glioblastomas, which can be extended to other aggressive tumor types.
Together, our results suggested that Cx43 acts as an inhibitory regulator of the activation of growth factor receptor downstream signaling pathways, indicating the potential of Cx43 as a marker for predicting the efficacy of EGFR inhibitor treatments for GBM.
Moreover, only a small proportion (17%) of our de novo glioblastomas exhibited EGFR amplification while a high proportion (62%) showed either p53 mutations or allelic loss of 17p13.1.
Collectively, these results identify a conserved pathway of oncogenic EGFR-induced DNA methylation-mediated transcriptional silencing of tumor suppressors that may have therapeutic benefits for oncogenic EGFR-mediated lung cancers and glioblastomas.