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

Sun, Yingyu; Zhang, Wei; Chen, Dongfeng LU ; Lv, Yuhong; Zheng, Junxiong; Lilljebjörn, Henrik LU ; Ran, Liang; Bao, Zhaoshi; Soneson, Charlotte LU and Olov Sjögren, Hans LU , et al. (2014) In Proceedings of the National Academy of Sciences of the United States of America 111(9). p.3538-3543
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 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... (More)

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.

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Proceedings of the National Academy of Sciences of the United States of America
volume
111
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9
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6 pages
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National Acad Sciences
external identifiers
  • scopus:84895814771
ISSN
0027-8424
DOI
10.1073/pnas.1313814111
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English
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yes
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b2f683ba-bb4b-46e0-90fb-6519abf25192
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2016-11-23 10:37:07
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2017-10-29 04:54:20
@article{b2f683ba-bb4b-46e0-90fb-6519abf25192,
  abstract     = {<p>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.</p>},
  author       = {Sun, Yingyu and Zhang, Wei and Chen, Dongfeng and Lv, Yuhong and Zheng, Junxiong and Lilljebjörn, Henrik and Ran, Liang and Bao, Zhaoshi and Soneson, Charlotte and Olov Sjögren, Hans and Salford, Leif G. and Ji, Jianguang and Frenc, Pim J. and Fioretos, Thoas and Jiang, Tao and Fan, Xiaolong},
  issn         = {0027-8424},
  language     = {eng},
  month        = {03},
  number       = {9},
  pages        = {3538--3543},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {A glioma classification scheme based on coexpression modules of EGFR and PDGFRA},
  url          = {http://dx.doi.org/10.1073/pnas.1313814111},
  volume       = {111},
  year         = {2014},
}