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

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A glioma classification scheme based on coexpression modules of EGFR and PDGFRA. / Sun, Yingyu; Zhang, Wei; Chen, Dongfeng; Lv, Yuhong; Zheng, Junxiong; Lilljebjörn, Henrik; Ran, Liang; Bao, Zhaoshi; Soneson, Charlotte; Olov Sjögren, Hans; Salford, Leif G.; Ji, Jianguang; Frenc, Pim J.; Fioretos, Thoas; Jiang, Tao; Fan, Xiaolong.

I: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, Nr. 9, 04.03.2014, s. 3538-3543.

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Sun, Yingyu ; Zhang, Wei ; Chen, Dongfeng ; Lv, Yuhong ; Zheng, Junxiong ; Lilljebjörn, Henrik ; Ran, Liang ; Bao, Zhaoshi ; Soneson, Charlotte ; Olov Sjögren, Hans ; Salford, Leif G. ; Ji, Jianguang ; Frenc, Pim J. ; Fioretos, Thoas ; Jiang, Tao ; Fan, Xiaolong. / A glioma classification scheme based on coexpression modules of EGFR and PDGFRA. I: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, Nr. 9. s. 3538-3543.

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TY - JOUR

T1 - A glioma classification scheme based on coexpression modules of EGFR and PDGFRA

AU - Sun, Yingyu

AU - Zhang, Wei

AU - Chen, Dongfeng

AU - Lv, Yuhong

AU - Zheng, Junxiong

AU - Lilljebjörn, Henrik

AU - Ran, Liang

AU - Bao, Zhaoshi

AU - Soneson, Charlotte

AU - Olov Sjögren, Hans

AU - Salford, Leif G.

AU - Ji, Jianguang

AU - Frenc, Pim J.

AU - Fioretos, Thoas

AU - Jiang, Tao

AU - Fan, Xiaolong

PY - 2014/3/4

Y1 - 2014/3/4

N2 - 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 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.

AB - 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 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.

UR - http://www.scopus.com/inward/record.url?scp=84895814771&partnerID=8YFLogxK

U2 - 10.1073/pnas.1313814111

DO - 10.1073/pnas.1313814111

M3 - Article

VL - 111

SP - 3538

EP - 3543

JO - Proceedings of the National Academy of Sciences

T2 - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 1091-6490

IS - 9

ER -