中国黏膜黑色素瘤的临床特点及基因突变分析

Clinical Characteristics and Mutation Landscape of Chinese Mucosal Melanoma

【目的】采用二代测序(NGS)检测黏膜黑色素瘤中的295个基因突变情况,分析黏膜黑色素瘤患者的基因突变谱及突变特点,探索潜在治疗靶点。【方法】组织标本来自2017年9月至2018年9月在中山大学肿瘤防治中心生物治疗科就诊的黏膜黑色素瘤患者,于我院分子诊断科行NGS检测295个基因变异。【结果】黑色素瘤主要驱动基因突变频率分别为BRAF 20%(5/25),KIT 20%(5/25),NRAS 12%(3/25),NF18%(2/25)。最常见的基因突变为MYC拷贝数增加(36%,9/25),其次为KDR拷贝数增加,突变率为24%(6/25)。DNA损伤修复,细胞周期,PI3K-mTOR,生长因子受体,MAPK,免疫应答和WNT/NOTCH相关通路广泛存在突变,突变率分别为76%(19/25),72%(18/25),56%(14/25),60%(15/25),36%(9/25),28%(7/25),24%(6/25)。可见多个靶向治疗靶点,如ATM,ATRX,EMSY,FANCI,RAD52,MET,PDGFRA,KDR,FLT4,ALK,ERBB3及ROS1等。【结论】中国黏膜黑色素瘤基因突变谱与皮肤型存在差异,且与西方人群不同,NGS测序可为黏膜黑色素瘤的治疗提供潜在治疗靶点。

【Objective】To use next generation sequencing(NGS)for examing 295 gene mutations in Chinese mucosal melanoma,and explore the mutation landscape of Chinese mucosal melanoma for potential therapeutic targets.【Methods】The specimens were from 25 mucosal melanoma patients from September 2017 to September 2018 in Biotherapy Center,Sun Yat-sen University Cancer Center. Mutations of 295 genes were detected by NGS sequencing in the Depart?ment of Molecular Diagnostics in our hospital.【Results】The mutation frequency of major driver genes of melanoma was:BRAF 20%(5/25),KIT 20%(5/25),NRAS 12%(3/25),and NF1 8%(2/25),respectively. The most common mutation was an increase copy number in MYC(9/25,36%),followed by an increase in KDR copy number,24%(6/25).DNA damage repair,cell cycle,PI3 K-mTOR,growth factor receptor,MAPK,immune response and WNT/NOTCH related pathways were widely mutated.Mutation rates were 76%(19/25),72%(18/25),56%(14/25),60%(15/25),36%(9/25),28%(7/25),and 24%(6/25),respectively. Multiple therapeutic targets were observed,such as ATM,ATRX,EMSY,FANCI,RAD52,MET,PDGFRA,KDR,FLT4,ALK,ERBB3 and ROS1.【Conclusion】Gene mutations in Chinese mucosal melanoma were different from that of Chinese cutaneousmelanomaandthat of Caucasians. NGS could provide potential therapeutic targets for the treatment of Chinese mucosal melanoma.