RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas
- Zhao-Shi Bao1,2,3,13,
- Hui-Min Chen4,13,
- Ming-Yu Yang4,13,
- Chuan-Bao Zhang1,2,3,
- Kai Yu4,
- Wan-Lu Ye4,
- Bo-Qiang Hu4,
- Wei Yan5,
- Wei Zhang2,3,
- Johnny Akers6,
- Valya Ramakrishnan6,
- Jie Li6,
- Bob Carter6,
- Yan-Wei Liu1,2,3,
- Hui-Min Hu1,
- Zheng Wang1,2,3,
- Ming-Yang Li1,2,3,
- Kun Yao3,7,
- Xiao-Guang Qiu3,8,
- Chun-Sheng Kang3,9,
- Yong-Ping You3,5,
- Xiao-Long Fan10,
- Wei Sonya Song1,11,
- Rui-Qiang Li4,
- Xiao-Dong Su4,
- Clark C. Chen6 and
- Tao Jiang1,2,3,11,12
- 1Beijing Neurosurgical Institute, Beijing 100050, China;
- 2Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China;
- 3Chinese Glioma Cooperative Group (CGCG), Beijing 100050, China;
- 4Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China;
- 5Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China;
- 6Center for Theoretical and Applied Neuro-Oncology (CTAN), Division of Neurosurgery, University of California, San Diego, California 92093, USA;
- 7Department of Pathology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China;
- 8Department of Radiotherapy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China;
- 9Department 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;
- 10Laboratory of Neuroscience and Brain Development, Beijing Key Laboratory of Gene Resources and Molecular Development, Beijing Normal University, Beijing 100875, China;
- 11Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing 100069, China;
- 12China National Clinical Research Center for Neurological Diseases, Beijing 100050, China
- Corresponding authors: taojiang1964{at}163.com, clarkchen{at}ucsd.edu, xdsu{at}pku.edu.cn
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↵13 These authors contributed equally to this work.
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.165126.113.
- Received October 27, 2013.
- Accepted August 14, 2014.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.