Co-expression modules of NF1, PTEN and sprouty enable distinction of adult diffuse gliomas according to pathway activities of receptor tyrosine kinases
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Wanyu Zhang1,*, Yuhong Lv1,7,*, Yang Xue1, Chenxing Wu2, Kun Yao3, Chuanbao Zhang4,5, Qiang Jin4,5, Rong Huang1, Jiuyi Li1, Yingyu Sun1, Xiaodong Su6, Tao Jiang4,5, Xiaolong Fan1
1Laboratory of Neuroscience and Brain Development, Beijing Key Laboratory of Gene Resources and Molecular Development, Beijing Normal University, Beijing, China
2Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China
3Department of Pathology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China
4Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
5Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
6Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China
7Current address: Department of Cell Biology, Hebei Medical University, Hebei, Shijiazhuang, China
*These authors have contributed equally to this work
Xiaolong Fan, email: [email protected]
Keywords: glioma, molecular classification, receptor tyrosine kinase
Received: December 03, 2015 Accepted: June 06, 2016 Published: July 1, 2016
Inter-individual variability causing elevated signaling of receptor tyrosine kinases (RTK) may have hampered the efficacy of targeted therapies. We developed a molecular signature for clustering adult diffuse gliomas based on the extent of RTK pathway activities. Glioma gene modules co-expressed with NF1 (NF1-M), Sprouty (SPRY-M) and PTEN (PTEN-M) were identified, their signatures enabled robust clustering of adult diffuse gliomas of WHO grades II-IV from five independent data sets into two subtypes with distinct activities of RAS-RAF-MEK-MAPK cascade and PI3K-AKT pathway (named RMPAhigh and RMPAlow subtypes) in a morphology-independent manner. The RMPAhigh gliomas were associated with poor prognosis compared to the RMPAlow gliomas. The RMPAhigh and RMPAlow glioma subtypes harbored unique sets of genomic alterations in the RTK signaling-related genes. The RMPAhigh gliomas were enriched in immature vessel cells and tumor associated macrophages, and both cell types expressed high levels of pro-angiogenic RTKs including MET, VEGFR1, KDR, EPHB4 and NRP1. In gliomas with major genomic lesions unrelated to RTK pathway, high RMPA signature was associated with short survival. Thus, the RMPA signatures capture RTK activities in both glioma cells and glioma microenvironment, and RTK signaling in the glioma microenvironment contributes to glioma progression.
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