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

Significance Classification of cancer provides crucial guidance for clinical treatment and mechanistic studies. Our work extends previous glioma classification studies in that we established EGFR module (EM)/PDGFRA module (PM) glioma classification scheme based on gene coexpression modules around key signaling pathways conserved in neural development and gliomagenesis. We identified coexpressed EM and PM genes as classifiers. Based on the EM and PM signatures, our classification scheme robustly assigns adult low-grade and high-grade diffuse gliomas into three major subtypes that are distinct in patient survival, and in transcriptomic and genomic patterns. Our work suggests that EM and PM genes may play currently unrecognized roles in gliomagenesis. EM/PM glioma classification scheme forms a framework toward establishing molecular diagnostic tools and identifying new therapeutic targets to combat gliomas. 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 EMlowPMlow 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 EMlowPMlow gliomas were associated with younger age at diagnosis and better prognosis. PM gliomas were enriched in the expression of oligodendrogenesis genes, whereas EMlowPMlow 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 subtype-specific 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.