A Tumor-Specific Neo-Antigen Caused by a Frameshift Mutation in BAP1 Is a Potential Personalized Biomarker in Malignant Peritoneal Mesothelioma.
A Tumor-Specific Neo-Antigen Caused by a Frameshift Mutation in BAP1 Is a Potential Personalized Biomarker in Malignant Peritoneal Mesothelioma.
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由 BAP1 移码突变引起的肿瘤特异性新抗原是恶性腹膜间皮瘤的潜在个性化生物标志物
DOI：
10.3390/ijms17050739
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发表时间：
2016-05-14
影响因子：
5.6
通讯作者：
Chen SQ
中科院分区：
文献类型：
--
作者：
Lai J;Zhou Z;Tang XJ;Gao ZB;Zhou J;Chen SQ
恶性腹膜间皮瘤（MPM）是一种侵略性罕见的恶性肿瘤与石棉暴露。更好地了解MPM的分子发病机制将有助于制定靶向治疗策略。癌基因靶向的深度测序进行肿瘤样本和配对的外周血DNA从恶性间皮瘤患者的腹膜。通过桑格法在转录水平验证了NOTCH 2、NSD 1、PDE 4DIP和ATP 10 B中的4个体细胞碱基替换和BAP 1中的1个插入移码突变。一个13个氨基酸的新肽的截短的Bap 1蛋白，这是由于这种新的移码突变产生的，预计将提交该患者的HLA-B蛋白。在兔体内制备了13肽的多克隆抗体。Western印迹结果显示抗体-新抗原具有良好的特异性，免疫组织化学（IHC）染色的新肽的抗体清楚地区分肿瘤细胞和正常细胞。对癌症体细胞突变目录（COSMIC）数据库的检索也显示，BAP 1中53.2%的突变是具有新肽形成的移码插入缺失。一个确定的肿瘤特异性新抗原可能是潜在的分子生物标志物的个性化诊断，以精确亚型罕见的恶性肿瘤，如MPM。
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.