title: Co-expression modules of NF1, PTEN and sprouty enable distinction of adult diffuse gliomas according to pathway activities of receptor tyrosine kinases.
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 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.
authors.affiliation: Laboratory of Neuroscience and Brain Development, Beijing Key Laboratory of Gene Resources and Molecular Development, Beijing Normal University, Beijing, China.
authors.forename: Wanyu
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Laboratory of Neuroscience and Brain Development, Beijing Key Laboratory of Gene Resources and Molecular Development, Beijing Normal University, Beijing, China.|Current address: Department of Cell Biology, Hebei Medical University, Hebei, Shijiazhuang, China.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Laboratory of Neuroscience and Brain Development, Beijing Key Laboratory of Gene Resources and Molecular Development, Beijing Normal University, Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China.
authors.forename: Chenxing
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Pathology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Yao
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.|Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Chuanbao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.|Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Jin
authors.affiliation: Laboratory of Neuroscience and Brain Development, Beijing Key Laboratory of Gene Resources and Molecular Development, Beijing Normal University, Beijing, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Huang
authors.affiliation: Laboratory of Neuroscience and Brain Development, Beijing Key Laboratory of Gene Resources and Molecular Development, Beijing Normal University, Beijing, China.
authors.forename: Jiuyi
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratory of Neuroscience and Brain Development, Beijing Key Laboratory of Gene Resources and Molecular Development, Beijing Normal University, Beijing, China.
authors.forename: Yingyu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Su
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.|Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Laboratory of Neuroscience and Brain Development, Beijing Key Laboratory of Gene Resources and Molecular Development, Beijing Normal University, Beijing, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Fan
mesh_terms: D000328:Adult; D016000:Cluster Analysis; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009367:Neoplasm Staging; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D020239:Receptor Cross-Talk; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome; D059016:Tumor Microenvironment
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D025542:Neurofibromin 1; D010750:Phosphoproteins; C486055:SPRY1 protein, human; C485561:SPRY2 protein, human; C499038:SPRY4 protein, human; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051059:PTEN Phosphohydrolase
keywords: glioma; molecular classification; receptor tyrosine kinase