title: RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas.
abstract: Studies of gene rearrangements and the consequent oncogenic fusion proteins have laid the foundation for targeted cancer therapy. To identify oncogenic fusions associated with glioma progression, we catalogued fusion transcripts by RNA-seq of 272 gliomas. Fusion transcripts were more frequently found in high-grade gliomas, in the classical subtype of gliomas, and in gliomas treated with radiation/temozolomide. Sixty-seven in-frame fusion transcripts were identified, including three recurrent fusion transcripts: FGFR3-TACC3, RNF213-SLC26A11, and PTPRZ1-MET (ZM). Interestingly, the ZM fusion was found only in grade III astrocytomas (1/13; 7.7%) or secondary GBMs (sGBMs, 3/20; 15.0%). In an independent cohort of sGBMs, the ZM fusion was found in three of 20 (15%) specimens. Genomic analysis revealed that the fusion arose from translocation events involving introns 3 or 8 of PTPRZ and intron 1 of MET. ZM fusion transcripts were found in GBMs irrespective of isocitrate dehydrogenase 1 (IDH1) mutation status. sGBMs harboring ZM fusion showed higher expression of genes required for PIK3CA signaling and lowered expression of genes that suppressed RB1 or TP53 function. Expression of the ZM fusion was mutually exclusive with EGFR overexpression in sGBMs. Exogenous expression of the ZM fusion in the U87MG glioblastoma line enhanced cell migration and invasion. Clinically, patients afflicted with ZM fusion harboring glioblastomas survived poorly relative to those afflicted with non-ZM-harboring sGBMs (P < 0.001). Our study profiles the shifting RNA landscape of gliomas during progression and reveled ZM as a novel, recurrent fusion transcript in sGBMs.
authors.affiliation: Beijing Neurosurgical Institute, Beijing 100050, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China; Chinese Glioma Cooperative Group (CGCG), Beijing 100050, China;
authors.forename: Zhao-Shi
authors.initials: ZS
authors.lastname: Bao
authors.affiliation: Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China; taojiang1964@163.com clarkchen@ucsd.edu xdsu@pku.edu.cn.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Chen
authors.affiliation: Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Ming-Yu
authors.initials: MY
authors.lastname: Yang
authors.affiliation: Beijing Neurosurgical Institute, Beijing 100050, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China; Chinese Glioma Cooperative Group (CGCG), Beijing 100050, China;
authors.forename: Chuan-Bao
authors.initials: CB
authors.lastname: Zhang
authors.affiliation: Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
authors.affiliation: Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Wan-Lu
authors.initials: WL
authors.lastname: Ye
authors.affiliation: Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Bo-Qiang
authors.initials: BQ
authors.lastname: Hu
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China;
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China; Chinese Glioma Cooperative Group (CGCG), Beijing 100050, China;
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology (CTAN), Division of Neurosurgery, University of California, San Diego, California 92093, USA;
authors.forename: Johnny
authors.initials: J
authors.lastname: Akers
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology (CTAN), Division of Neurosurgery, University of California, San Diego, California 92093, USA;
authors.forename: Valya
authors.initials: V
authors.lastname: Ramakrishnan
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology (CTAN), Division of Neurosurgery, University of California, San Diego, California 92093, USA;
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology (CTAN), Division of Neurosurgery, University of California, San Diego, California 92093, USA;
authors.forename: Bob
authors.initials: B
authors.lastname: Carter
authors.affiliation: Beijing Neurosurgical Institute, Beijing 100050, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China; Chinese Glioma Cooperative Group (CGCG), Beijing 100050, China;
authors.forename: Yan-Wei
authors.initials: YW
authors.lastname: Liu
authors.affiliation: Beijing Neurosurgical Institute, Beijing 100050, China;
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Hu
authors.affiliation: Beijing Neurosurgical Institute, Beijing 100050, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China; Chinese Glioma Cooperative Group (CGCG), Beijing 100050, China;
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Beijing Neurosurgical Institute, Beijing 100050, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China; Chinese Glioma Cooperative Group (CGCG), Beijing 100050, China;
authors.forename: Ming-Yang
authors.initials: MY
authors.lastname: Li
authors.affiliation: Chinese Glioma Cooperative Group (CGCG), Beijing 100050, China; Department of Pathology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China;
authors.forename: Kun
authors.initials: K
authors.lastname: Yao
authors.affiliation: Chinese Glioma Cooperative Group (CGCG), Beijing 100050, China; Department of Radiotherapy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China;
authors.forename: Xiao-Guang
authors.initials: XG
authors.lastname: Qiu
authors.affiliation: Chinese Glioma Cooperative Group (CGCG), Beijing 100050, China; Department of Neurosurgery, Tianjin Medical University General Hospital, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300052, China;
authors.forename: Chun-Sheng
authors.initials: CS
authors.lastname: Kang
authors.affiliation: Chinese Glioma Cooperative Group (CGCG), Beijing 100050, China; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China;
authors.forename: Yong-Ping
authors.initials: YP
authors.lastname: You
authors.affiliation: Laboratory of Neuroscience and Brain Development, Beijing Key Laboratory of Gene Resources and Molecular Development, Beijing Normal University, Beijing 100875, China;
authors.forename: Xiao-Long
authors.initials: XL
authors.lastname: Fan
authors.affiliation: Beijing Neurosurgical Institute, Beijing 100050, China; Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing 100069, China;
authors.forename: Wei Sonya
authors.initials: WS
authors.lastname: Song
authors.affiliation: Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Rui-Qiang
authors.initials: RQ
authors.lastname: Li
authors.affiliation: Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China; taojiang1964@163.com clarkchen@ucsd.edu xdsu@pku.edu.cn.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Su
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology (CTAN), Division of Neurosurgery, University of California, San Diego, California 92093, USA; taojiang1964@163.com clarkchen@ucsd.edu xdsu@pku.edu.cn.
authors.forename: Clark C
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Beijing Neurosurgical Institute, Beijing 100050, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China; Chinese Glioma Cooperative Group (CGCG), Beijing 100050, China; Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing 100069, China; China National Clinical Research Center for Neurological Diseases, Beijing 100050, China taojiang1964@163.com clarkchen@ucsd.edu xdsu@pku.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000556:secondary; D005910:Glioma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D057809:HEK293 Cells; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D000077204:Temozolomide; D014178:Translocation, Genetic; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D015514:Oncogene Proteins, Fusion; D003606:Dacarbazine; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C516895:PTPRZ1 protein, human; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D000077204:Temozolomide