title: 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 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.
authors.affiliation: Beijing Key Laboratory of Gene Resource and Molecular Development, Laboratory of Neuroscience and Brain Development, Beijing Normal University, Beijing 100875, China.
authors.forename: Yingyu
authors.initials: Y
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Chen
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Lv
authors.forename: Junxiong
authors.initials: J
authors.lastname: Zheng
authors.forename: Henrik
authors.initials: H
authors.lastname: Lilljebjörn
authors.forename: Liang
authors.initials: L
authors.lastname: Ran
authors.forename: Zhaoshi
authors.initials: Z
authors.lastname: Bao
authors.forename: Charlotte
authors.initials: C
authors.lastname: Soneson
authors.forename: Hans Olov
authors.initials: HO
authors.lastname: Sjögren
authors.forename: Leif G
authors.initials: LG
authors.lastname: Salford
authors.forename: Jianguang
authors.initials: J
authors.lastname: Ji
authors.forename: Pim J
authors.initials: PJ
authors.lastname: French
authors.forename: Thoas
authors.initials: T
authors.lastname: Fioretos
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Fan
mesh_terms: D000367:Age Factors; D000818:Animals; D002681:China; D016000:Cluster Analysis; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005910:Glioma / Q000145:classification* / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D058953:Neural Stem Cells / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D066246:ErbB Receptors; D020796:Receptor, Platelet-Derived Growth Factor alpha