ARHGAP21 S1075X基因突变在肢端型黑色素瘤发病中的作用及机制研究

Acral melanoma is an infrequent subtype in Caucasians, but the percentage is significantly higher in Asia, whereas the incidence of acral melanoma in Chinese is 41.8%. There is still no efficient treatment therapy for acral melanoma patients, and the prognosis is very poor. Screening specific gene aberrations and application of molecular targeted therapy is the primary treatment for advanced melanoma. However, the investigation about the targeted treatment of acral melanoma is limited. We have found out that 3% Chinese acral melanoma patients harbored S1075X mutations in ARHGAP21 and all mutations were found in metastasis tissues, suggests that ARHGAP21 S1075X mutation maybe a risk factor for poor prognosis. It has been reported that ARHGAP21 has RhoGAP activity, but its function in cancer has been poorly investigated. We will further investigate the biological functions and mechanisms of ARHGAP21 S1075X mutations on melanocytes transformation. This study will provide clues to clarify the molecular mechanisms of ARHGAP21 S1075X mutation in melanomas, and might find out new treatment target for acral melanomas.

肢端型黑色素瘤在白种人中极为少见，但在黄种人中发病率较高，中国肢端型黑色素瘤发病率为41.8%，针对该类患者尚无有效治疗手段，患者预后极差。对特定靶点开展基因变异筛查已成为晚期黑色素瘤的首要治疗策略，尽管如此，国际上针对肢端型黑色素瘤靶向治疗的专门研究鲜有报道。申请者前期对200例肢端型黑色素瘤组织标本进行基因突变检测，发现了一个既往未被报道过的频发突变，约3%肢端型黑色素瘤患者存在ARHGAP21基因S1075X截短型突变，且全部存在于转移灶标本中，提示可能为预后不良的危险因素之一。ARHGAP21具有Rho-GTP酶激活蛋白的活性，但其在肿瘤中的作用尚未可知。本项目拟深入研究ARHGAP21 S1075X突变在黑色素细胞恶性转化中的生物学功能，并澄清其诱导黑色素细胞生物学特性发生变化的作用机制，以期为明确S1075X突变在黑色素瘤中的分子机制，寻找肢端型黑色素瘤治疗新靶点提供实验线索。

肢端型黑色素瘤在白种人中极为少见，但在黄种人中发病率较高，中国肢端型黑色素瘤发病率为41.8%，针对该类患者尚无有效治疗手段，患者预后极差。对特定靶点开展基因变异筛查已成为晚期黑色素瘤的首要治疗策略，尽管如此，国际上针对肢端型黑色素瘤靶向治疗的专门研究鲜有报道。项目组为完善肢端型黑色素瘤基因变异谱，寻找符合中国特色的肢端型黑色素瘤治疗方案，探索了ARHGAP21、CDK4通路主要分子、TERT、DTL等基因在肢端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。为深入研究肢端型黑色素瘤转移的分子机制，通过全基因组表达谱芯片筛选出肢端型黑色素瘤转移相关的分子标志物CDCA5、GTSE1，进而探究其在肢端型黑色素瘤转移进程中的生物学功能及临床意义。为寻找肢端型黑色素瘤治疗新靶点提供实验线索。共发表SCI论著17篇，累计影响因子101.266分，培养博士研究生7名，硕士研究生2名。

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