A glioma classification scheme based on coexpression modules of EGFR and PDGFRA

Abstract

We hypothesized that key signaling pathways of glioma genesis might enable the molecular classification of gliomas. Gene coexpression modules around epidermal growth factor receptor (EGFR) (EM, 29 genes) or platelet derived growth factor receptor A (PDGFRA) (PM, 40 genes) in gliomas were identified. Based on EM and PM expression signatures, nonnegative matrix factorization reproducibly clustered 1,369 adult diffuse gliomas WHO grades II-IV from four independent databases generated in three continents, into the subtypes (EM, PM and EM low PM low gliomas) in a morphology-independent manner. Besides their distinct patterns of genomic alterations, EM gliomas were associated with higher age at diagnosis, poorer prognosis, and stronger expression of neural stem cell and astrogenesis genes. Both PM and EM low PM low gliomas were associated with younger age at diagnosis and better prognosis. PM gliomas were enriched in the expression of oligodendrogenesis genes, whereas EM low PM low gliomas were enriched in the signatures of mature neurons and oligodendrocytes. The EM/PM-based molecular classification scheme is applicable to adult low-grade and high-grade diffuse gliomas, and outperforms existing classification schemes in assigning diffuse gliomas to subtypes with distinct transcriptomic and genomic profiles. The majority of the EM/PM classifiers, including regulators of glial fate decisions, have not been extensively studied in glioma biology. Subsets of these classifiers were coexpressed in mouse glial precursor cells, and frequently amplified or lost in an EM/PM glioma subtypespecific manner, resulting in somatic copy number alteration-dependent gene expression that contributes to EM/PM signatures in glioma samples. EM/PM-based molecular classification provides a molecular diagnostic framework to expedite the search for new glioma therapeutic targets.

Long Noncoding RNA NEAT1, Regulated by the EGFR Pathway, Contributes to Glioblastoma Progression Through the WNT/β-Catenin Pathway by Scaffolding EZH2

“…EGFRvIII, the most common EGFR mutant, is found in 50%-60% cases, strongly indicating a poor survival prognosis (2)(3)(4). In 2014, EGFR module (EM)/PDGFRA (platelet-derived growth factor receptor A) (PM)-based molecular classification was performed and provided a molecular diagnostic framework to expedite the search for new glioma therapeutic targets (5). Furthermore, the molecular mechanism underlying glioma progression remains poorly understood.…”

High expression of N-myc (and STAT) interactor predicts poor prognosis and promotes tumor growth in human glioblastoma

“…Therefore, personalized treatment regimens may be more effective for patients. Recently, substantial efforts have been made in the identification of molecular subtypes [13, 14] and biomarkers associated with GBM patients' survival [15-17], to better understand the pathogenesis of GBM. Several public resources, such as the Repository of Molecular Brain Neoplasia Data (Rembrandt) database [18] and The Cancer Genome Atlas (TCGA) network [19] have provided insight into the molecular carcinogenesis of GBM, affording opportunities for researchers to correlate gene expression with multidimensional clinical and molecular features of patients [15, 16, 20-22].…”

Identification of Postoperative Margins of Glioblastoma Multiforme Using Gold Nanoparticles Conjugated to Epidermal Growth Factor Antibodies

“…In one study, GNPs were used for radiofrequency ablation of pancreatic and colorectal adenocarcinomas in animal models [33]. Although the high levels of EGFR in some forms of GBM also make it an accurate and desirable therapeutic target, current therapies targeting EGFR, including tyrosine kinase inhibitors and RNA interference, have proved to be ineffective [7,8,34]. Therefore, attention is being addressed to other means: the delivery of novel antitumor agents across the blood-brain barrier, gene therapy, and brain tumor vaccines [35][36][37].…”

“…As a result of these findings, attention has been addressed to overexpression of the EGFR protein as a potential prognostic indicator in GBM [5]. However, its accuracy remains unclear [3,5,7,8].…”