Diagnostic Ability of Serum microRNA Classification in Diffuse Glioma: A Retrospective Comprehensive Analysis with Case-Control Study

Abstract

Background: The ability of serum microRNAs (miRNAs) to detect diffuse gliomas remains unclear. Here, we searched for serum miRNAs capable of distinguishing diffuse gliomas from non-cancer individuals. The potential of miRNAs to discriminate between glioblastoma (GBM), primary central nervous system lymphoma (PCNSL) and metastatic brain tumours (Meta), and to define isocitrate dehydrogenase 1 and 2 gene (IDH1/2) mutation status, was also examined. Methods: A comprehensive analysis of 2,565 serum miRNA profiles in 774 samples, including 157 diffuse gliomas, 42 PCNSLs, 28 Metas, 39 other central nervous system diseases and 508 non-cancer controls collected between August 2008 and May 2016, was performed. IDH1/2 mutation status was confirmed in 129 diffuse gliomas. Samples were randomly divided into training and validation sets to develop and evaluate discrimination models between diffuse gliomas and non-cancer controls, between GBM, PCNSL, and Meta, and between IDH1 and 2 mutations. Findings: A combination of five miRNAs (miR-4763-3p, miR-1915-3p, miR3679-5p, miR-6087 and miR-197-5p) discriminated diffuse gliomas from noncancer individuals with a sensitivity of 0·98, a specificity of 1·00 and an area under the curve (AUC) of 0·99. A discrimination model consisting of 48 miRNAs detected GBM in 94·1%, Meta in 80% and PCNSL in 50% of participants. A combination of three miRNAs (miR-128-2-5p, miR-3195 and miR-22-3p) predicted IDH1/2 mutation status, although the diagnostic performance was not high (sensitivity: 0·29, specificity: 0·97 and AUC: 0·78). Interpretation: The five-miRNA combination model effectively distinguished diffuse gliomas from non-cancer individuals, and may be useful as a low-invasive screening tool to help decision making regarding further neuroradiological examinations. MiRNAs could identify GBM and Meta, whereas they showed limited ability to identify PCNSL and to predict IDH1/2 mutation status. Funding Statement: This study was financially supported through a “Development of Diagnostic Technology for Detection of miRNA in Body Fluids” grant from the Japan Agency for Medical Research and Development (to TO). Declaration of Interests: Dr. Ohno reports grants from Japanese-German Exchange Program of the Japanese Neurosurgical society, outside the submitted work. Dr. Matsuzaki has nothing to disclose. Dr. Kawauchi reports personal fees from Toray Industries, Inc., outside the submitted work. Dr. Aoki reports personal fees from DYNACOM Co., Ltd., outside the submitted work. Dr. Miura reports personal fees from DYNACOM Co., Ltd., outside the submitted work. Dr. Takizawa reports personal fees from Toray Industries, Inc., during the conduct of the study. Dr. Kato reports other from ONO, other from MSD, other from Beigene, personal fees from Eli Lilly, other from Shionogi, outside the submitted work. Dr. Matsushita has nothing to disclose. Dr. Takahashi has nothing to disclose. Dr. Miyaktia has nothing to disclose. Dr. Ichimura reports grants and other from Chugai Pharmaceutical Co., Ltd., grants from Eisai Co., Ltd., grants and other from Daiichi Sankyo Co.Ltd., outside the submitted work. Dr. Narita reports grants from Japan Agency for Medical Research and Development, during the conduct of the study; grants and personal fees from Chugai Pharmaceutical co., grants and personal fees from MSD, grants and personal fees from Eisai, grants and personal fees from Toshiba, grants from SBI pharma, grants from Glaxo, grants and personal fees from Abbive, grants from Ono, grants from Stella-pharma, grants and personal fees from Ohtuka, grants from Meiji-seika, grants and personal fees from Daiichi-Sankyo, outside the submitted work. Dr. Ochiya reports grants from Japan Agency for Medical Research and Development, during the conduct of the study; grants from Kewpie Corporation, grants from Takeda Pharmaceutical Company Limited., grants from BioMimetics Sympathies. Inc, grants from Rohto Pharmaceutical Co., Ltd., grants from Inter Stem Co., Ltd., non-financial support from Japan Atherosclerosis Research Foundation, grants from ONO PHARMACEUTICAL CO., LTD., grants from Daiichi-Sankyo Company, Limited, non-financial support from JVC KENWOOD Corporation, non-financial support from Sysmex Corporation, grants from Astellas Pharma, grants from Kyowa Medex Co., Ltd. , non-financial support from Theoria science, outside the submitted work. Ethics Approval Statement: The study was approved by the NCCH Institutional Review Board (2004-066, 2015-376, 2016-099, 2016-249) and the Research Committee of Medical Corporation Shintokai Yokohama Minoru Clinic (6019-18-3772). Written informed consent was obtained from each participant.