m6A相关长链非编码RNA在黑色素瘤患者预后中的作用研究  

Role of m6A Related Long-chain Noncoding RNA in the Prognosis of Patients with Melanoma

作　　者：张玉艳[1] 黄亚鹏 陈倩梅 龙惠[1] 黄久遂[1] 朱慧兰[1] ZHANG Yuyan;HUANG Yapeng;CHEN Qianmei;LONG Hui;HUANG Jiusui;ZHU Huilan(Guangzhou Institute of Dermatology,Guangzhou,Guangdong 510095,China;The First Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong 510080,China)

机构地区：[1]广州市皮肤病防治所,广东广州510095 [2]中山大学附属第一医院,广东广州510080

出　　处：《今日药学》2022年第6期453-461,共9页Pharmacy Today

基　　金：广州市卫生和计划生育科技项目(20181A011059)。

摘　　要：目的探讨N6甲基腺苷(m6A)甲基化修饰相关的长链非编码RNA(lncRNA)在黑色素瘤预后中的作用以及可能的机制。方法从癌症基因组图谱(TCGA)数据库中下载黑色素瘤患者的测序和临床数据并进行整合,利用皮尔逊相关系数分析获得与m6A甲基化修饰酶相关的lncRNA,并基于这些lncRNA在肿瘤患者中的表达通过一致性聚类分析确定黑色素瘤患者的不同分子亚型,进一步分析患者亚型之间肿瘤微环境的差异分布,筛选存在预后价值的lncRNA并进行基因评分(gene score=∑PC1i+∑PC2i),进而分析高/低评分患者之间的差异表达基因与分子通路。结果通过获取的468例黑色素瘤患者的基因测序结果和临床数据,筛选出453个与m6A甲基化修饰酶相关的lncRNA,并基于这些lncRNA在肿瘤患者中确定出两种分子亚型—cluster1与clueter2,其中cluster1的预后明显差于cluster2(P<0.001),而且亚型之间的肿瘤微环境存在明显差异,其中M2型巨噬细胞和滤泡辅助性T细胞在cluster1中表达明显高于cluster2(P<0.05),而静息性NK杀伤细胞、激活的记忆CD4T细胞及M1型巨噬细胞在cluster1中表达明显低于cluster2(P<0.05)。同时获得85个存在预测预后价值的m6A-lncRNA(P<0.05),基因评分高的情况下黑色素瘤患者预后更佳,且高评分患者中的浸润性免疫细胞更为活跃,对于应用PD1与CTLA4免疫抑制剂治疗的应答率更高,此外,高/低评分患者间存在大量差异表达基因,并富集在T细胞激活等免疫细胞调控通路。结论本研究显示m6A甲基转移酶相关lncRNAs与黑色素瘤的预后密切相关,m6A-lncRNAs可能在黑色素瘤肿瘤微环境分布中发挥着一定的调控功能,并可有效预测其对PD1与CTLA4免疫抑制剂治疗反应。OBJECTIVE To investigate the role and possible mechanism of long-chain noncoding RNA(lncRNA)related to the methylation modification of N6 methyladenosine(m6 A)in the prognosis of melanoma.METHODS This study first downloaded and integrated the sequencing and clinical data of melanoma patients from the Cancer Genome Atlas(TCGA)database.The lncRNAs relatedto m6A methylation modifying enzymes were obtained by Pearson correlation coefficient analysis.Then,based on these lncRNAs,aconsistent clustering algorithm was performed in tumor patients to determine molecular subtypes,the potential differential pathways between subtypes were analyzed,and the differential distribution of the tumor microenvironment between them was analyzed.lncRNAs with prognostic value were screened and scored(gene score=∑PC1i+∑PC2i),and the differentially expressed genes and molecular pathways between high/low score patients were screened.RESULTS Based on the gene sequencing results and clinical data of 468 melanoma patients,453 lncRNAs related to m6A methylation modifying enzyme were screened.Based on these lncRNAs,two molecular subtypes cluster1 and cluster2 were identified in tumor patients.The prognosis of cluster1 was significantly worse than that of cluster2(P<0.001),and there was significant difference in tumor microenvironment between subtypes.The expressions of M2 macrophages and follicular helper T cells in cluster1 were significantly higher than that in cluster2(P<0.05),while the expressions of resting NK killercells,activated memory CD4 T cells and M1 macrophages in cluster1 were significantly lower than that in cluster2(P<0.05).85 m6A-lncRNAs with prognostic value were obtained(P<0.05).Melanoma patients with high gene scores had a better prognosis,more activeinfiltrating immune cells,and a higher response rate in PD1 and CTLA4 immunosuppressants therapy.In addition,there were large number of differentially expressed genes among patients between high and low scores,which were enriched in immune cell pathways suchas T cells activat

关 键 词：黑色素瘤 N6甲基腺苷(m6A)甲基化修饰 长链非编码RNA 免疫调节 基因评分 

分 类 号：R966[医药卫生—药理学]