title: A Tumor-Specific Neo-Antigen Caused by a Frameshift Mutation in BAP1 Is a Potential Personalized Biomarker in Malignant Peritoneal Mesothelioma.
abstract: Malignant peritoneal mesothelioma (MPM) is an aggressive rare malignancy associated with asbestos exposure. A better understanding of the molecular pathogenesis of MPM will help develop a targeted therapy strategy. Oncogene targeted depth sequencing was performed on a tumor sample and paired peripheral blood DNA from a patient with malignant mesothelioma of the peritoneum. Four somatic base-substitutions in NOTCH2, NSD1, PDE4DIP, and ATP10B and 1 insert frameshift mutation in BAP1 were validated by the Sanger method at the transcriptional level. A 13-amino acids neo-peptide of the truncated Bap1 protein, which was produced as a result of this novel frameshift mutation, was predicted to be presented by this patient's HLA-B protein. The polyclonal antibody of the synthesized 13-mer neo-peptide was produced in rabbits. Western blotting results showed a good antibody-neoantigen specificity, and Immunohistochemistry (IHC) staining with the antibody of the neo-peptide clearly differentiated neoplastic cells from normal cells. A search of the Catalogue of Somatic Mutations in Cancer (COSMIC) database also revealed that 53.2% of mutations in BAP1 were frameshift indels with neo-peptide formation. An identified tumor-specific neo-antigen could be the potential molecular biomarker for personalized diagnosis to precisely subtype rare malignancies such as MPM.
authors.affiliation: Institute of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China. laijun@zju.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Lai
authors.affiliation: Institute of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China. zhouzhan@zju.edu.cn.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Institute of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China. txjgyqy@163.com.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Tang
authors.affiliation: Department of Obstetrics and Gynecology, Yuyao People's Hospital, 800 Chengdong Road, Yuyao 315400, China. gzb-gx@163.com.
authors.forename: Zhi-Bin
authors.initials: ZB
authors.lastname: Gao
authors.affiliation: Institute of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China. zhoujie127@zju.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Institute of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China. chenshuqing@zju.edu.cn.
authors.forename: Shu-Qing
authors.initials: SQ
authors.lastname: Chen
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D015153:Blotting, Western; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics*; D008285:Major Histocompatibility Complex; D008654:Mesothelioma / Q000235:genetics*; D000086002:Mesothelioma, Malignant; D008954:Models, Biological; D008970:Molecular Weight; D010534:Peritoneal Neoplasms / Q000235:genetics*; D057285:Precision Medicine; D015203:Reproducibility of Results; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000737:chemistry / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; C400134:BAP1 protein, human; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase
keywords: BAP1; mesothelioma; neo-antigen; personalized immunotherapy target