Co-expression modules of NF1, PTEN and sprouty enable distinction of adult diffuse gliomas according to pathway activities of receptor tyrosine kinases

Abstract

// Wanyu Zhang 1, * , Yuhong Lv 1, 7, * , Yang Xue 1 , Chenxing Wu 2 , Kun Yao 3 , Chuanbao Zhang 4, 5 , Qiang Jin 4, 5 , Rong Huang 1 , Jiuyi Li 1 , Yingyu Sun 1 , Xiaodong Su 6 , Tao Jiang 4, 5 , Xiaolong Fan 1 1 Laboratory of Neuroscience and Brain Development, Beijing Key Laboratory of Gene Resources and Molecular Development, Beijing Normal University, Beijing, China 2 Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China 3 Department of Pathology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China 4 Beijing Neurosurgical Institute, Capital Medical University, Beijing, China 5 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 6 Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China 7 Current address: Department of Cell Biology, Hebei Medical University, Hebei, Shijiazhuang, China * These authors have contributed equally to this work Correspondence to: Xiaolong Fan, email: XFan@bnu.edu.cn Keywords: glioma, molecular classification, receptor tyrosine kinase Received: December 03, 2015      Accepted: June 06, 2016      Published: July 1, 2016 ABSTRACT 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 RMPA high and RMPA low subtypes) in a morphology-independent manner. The RMPA high gliomas were associated with poor prognosis compared to the RMPA low gliomas. The RMPA high and RMPA low glioma subtypes harbored unique sets of genomic alterations in the RTK signaling-related genes. The RMPA high 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.