CCND1拷贝数扩增在肢端型黑色素瘤发生发展中的作用及机制研究

Acral melanoma is characterized by rapid progression and poor prognosis, accounting for 47.5-65% of the total number of Caucasian melanoma patients.CCND1 is an important regulatory gene in the cell cycle, and it is a "bridge molecule" that can link targeted therapy with immunotherapy.Overexpression of CCND1 is closely related to the pathogenesis and development of tumors.. My previous study found that the proportion of patients harboring CCND1 copy number amplification was 35.8% in 572 acral melanoma patients.CCND1 amplification is an independent prognostic factor affecting PFS in acral melanoma.However, the role of CCND1 copy number amplification in the malignant transformation of acral melanoma has not been reported.By constructing CCND1 interference and overexpression cell models, performing RNA sequencing, bioinformatics analysis, combined with previous studies and database predictions, we hypothesized that the CCND1-MEP50/PRMT5 pathway may affect the malignant phenotype of acral melanoma.. Based on the above, I intend to conduct a study on the role and molecular mechanism of CCND1 copy number amplification in acral melanoma. This study can provide new ideas for the pathogenesis of acral melanoma, and provide a theoretical basis and experimental basis for further exploration of CDK inhibitors combined with PRMT5 inhibitors for the treatment of acral melanoma.

肢端型黑色素瘤进展快，预后差，占黄种人黑色素瘤患者总数的47.5～65%。CCND1是细胞周期重要调节基因，是联系靶向治疗和免疫治疗的桥梁分子，CCND1的过度表达参与肿瘤的发生发展。. 申请者前期研究发现，572例肢端型黑色素瘤中CCND1拷贝数扩增率高达35.8%，CCND1扩增是影响肢端型黑色素瘤PFS的独立预后因素。但CCND1拷贝数扩增在肢端型黑色素瘤恶性转化中的作用尚未见报道。申请者通过构建CCND1干扰、过表达细胞模型，RNA-seq、生信分析，结合文献和数据库预测，提示CCND1-MEP50/PRMT5通路可能影响肢端型黑色素瘤的恶性转化。基于以上，申请者拟开展CCND1拷贝数扩增在肢端型黑色素瘤中的作用及分子机制研究，为研究肢端型黑色素瘤发病机制提供新思路，为进一步探索细胞周期抑制剂联合PRMT5抑制剂应用于肢端型黑色素瘤治疗提供理论依据和实验基础。

黑色素瘤是由黑色素细胞恶变导致的肿瘤，恶性程度高、进展快、预后差，其发病率在全球范围内逐年上升。晚期黑色素瘤治疗手段有限，如何提高晚期黑色素瘤疗效是临床面临的困境。项目负责人前期研究发现，肢端型黑色素瘤中细胞周期调节基因CCND1拷贝数扩增率高达35.8%，CCND1扩增是影响肢端型黑色素瘤PFS的独立预后因素。但CCND1拷贝数扩增在肢端型黑色素瘤恶性转化中的作用尚未见报道。. 在项目执行过程中，项目负责人探讨了肿瘤细胞周期调节基因CCND1、CCNE1拷贝数扩增特点、ERBB通路变异的人群特点及对黑色素瘤生物学功能的影响；基于临床队列信息和测序数据，完成了3项中国人群黑色素瘤患者免疫治疗疗效预测生物标志物研究。在基金资助下，共发表SCI论文4篇，协助培养 1名研究生。本项目中，基于患者样本建立的患者基因变异特征和疗效预测模型，可以建立更加科学的筛选潜在获益人群，建立合理的治疗后随访方案，为临床治疗决策和临床试验设计提供依据。