粘膜型黑色素瘤中DGKζ的功能及其作为潜在治疗靶点的研究

In recent years, the incidence of melanoma has increased significantly. It is estimated that there are over 20,000 new cases every year. Mucosal melanoma is the second frequent subtype of melanoma in Asia, accounting for almost 25% of all melanomas. At present, research on mucosal melanoma internationally has been restricted. There exist no guidelines for the treatment of mucosal melanoma. Screening mutation of potential targets to select targeted agent has been the primary treatment strategy of melanoma, but little is known about genetic underpinnings of mucosal melanoma. Applicants have been developed genomic profiling of mucosal melanoma by whole genome sequencing. It is found that the hotspot mutations frequency of DGKζ was almost 20% in mucosal melanoma tumors, which has not been published. However, it is not clear that the functional consequences of these mutations. This study intends to explore the biological function of DGKζ and high frequency mutation, and analyzes related protein components changes. Further explain the effects of DGKζ mutants on signaling pathway and select effective inhibitors for mucosal melanoma patients, this may be a potential avenue of targeted treatment for patients harboring this gene mutation.

黑色素瘤在中国的发病率呈上升趋势，每年新发病人数已超过2万人，其中粘膜型是黄色人种黑色素瘤患者中第二常见亚型，发病比例约占1/4。粘膜型黑色素瘤具有突变负荷高、预后差等特点，针对该型黑色素瘤的治疗缺乏可遵循的指南。对特定靶点开展基因变异筛查进而选择靶向药物是晚期黑色素瘤治疗的首选策略之一，但粘膜型黑色素瘤的遗传变异谱及潜在治疗靶点尚不清楚。前期在粘膜型黑色素瘤中开展了全基因组测序，首次发现约20%的粘膜型黑色素瘤患者携带DGKζ基因高频突变，但DGKζ在粘膜型黑色素瘤中的功能未知，新发现的突变对DGKζ功能以及相关信号通路的影响也需澄清。本项目拟探讨DGKζ及其高频突变的生物学功能；解析该突变导致的DGKζ蛋白质复合物组分改变，深入阐释与突变相关的信号通路活性的变化；以此为线索，利用PDX模型筛选靶向药物，探讨将DGKζ做为粘膜型黑色素瘤治疗靶点的可能性，为有效治疗方案的选择奠定基础。

黑色素瘤在中国的发病率呈上升趋势，每年新发病人数已超过2万人，其中黏膜型是亚裔人种黑色素瘤患者中第二常见亚型，发病比例约占1/4。黏膜型黑色素瘤具有突变负荷高、预后差等特点，针对该型黑色素瘤的治疗缺乏可遵循的指南。对特定靶点开展基因变异筛查进而选择靶向药物是晚期黑色素瘤治疗的首选策略之一，但粘膜型黑色素瘤的遗传变异谱及潜在治疗靶点尚不清楚。项目组为完善黏膜型黑色素瘤的遗传变异谱，探索潜在治疗靶点，寻找符合中国特色的黑色素瘤治疗方案。开展了以DGKζ，CDK4，miRNA 等靶点在黏膜黑色素瘤中的变异情况，及与临床参数、预后及疗效之间的相关性，并初步探索其在黏膜黑色素瘤中的作用机制，以此为线索，利用PDX模型筛选靶向药物。为探寻黏膜型黑色素瘤治疗新靶点奠定基础。共发表SCI论著21篇，累计影响因子131.662分，作为研究生导师共培养硕士研究生4名，毕业硕士研究生2名。