膀胱尿路上皮癌中KDM6A突变与预后和免疫微环境的分析

Analysis of KDM6A mutation,prognosis and immune microenvironment in bladder urothelial carcinoma

目的通过生物信息学分析结合临床样本检测,寻找膀胱尿路上皮癌(BLCA)中关键基因的突变和机制探讨。方法下载TCGA(406例肿瘤组织和19例癌旁组织)和GTEx(21例癌旁组织)数据库中全部BLCA病例数据集的基因突变数据、转录组数据和临床数据。收集BLCA手术临床样本共32例,实时荧光定量聚合酶链反应(PCR)检测基因表达。结果91.42%的患者存在突变,其中错义突变、单核苷酸变异和C>T突变为主要突变类型,突变排在前5位的基因分别为TP53(47%)、TTN(45%)、KMT2D(29%)、MUC16(28%)、KDM6A(26%)。TCGA和临床样本中,KDM6A突变型表达水平均显著高于野生型(P=0.008、0.007)。KDM6A野生型的总体生存期(OS)和无进展生存期(PFS)均大于突变型(P=0.028、0.035)。进一步研究发现,KDM6A的表达与CD8+T细胞(r=0.22,P=0.039)、巨噬细胞(r=0.31,P=0.032)和内皮细胞(r=0.26,P=0.002)水平均呈显著正相关。结论BLCA中KDM6A的突变与预后和免疫微环境密切相关,KDM6A突变可能是BLCA的潜在治疗靶标。

Objective To identify key gene mutations and explore their mechanisms in bladder urothelial carcinoma(BLCA)through bioinformatics analysis combined with clinical sample testing.Methods Gene mutation data,transcriptome data,and clinical data for all BLCA cases were downloaded from the TCGA database(406 tumor tissues and 19 adjacent non-cancer tissues)and GTEx database(21 adjacent non-cancer tissues).A total of 32 clinical samples from BLCA surgeries were collected,and gene expression was measured using real-time quantitative polymerase chain reaction(PCR).Results Mutations were found in 91.42%of the patients,with missense mutations,single nucleotide variants,and C>T transitions being the predominant types.The top five mutated genes were TP53(47%),TTN(45%),KMT2D(29%),MUC16(28%),and KDM6A(26%).In both TCGA and clinical samples,the expression levels of mutant KDM6A were significantly higher than those of the wild type(P=0.008,0.007).The patients with wild-type KDM6A had a longer overall survival(OS)and progression-free survival(PFS)than those with the mutation(P=0.028,0.035).Further studies revealed that the expression of KDM6A was significantly positively correlated with the levels of CD8+T cells(r=0.22,P=0.039),macrophages(r=0.31,P=0.032),and endothelial cells(r=0.26,P=0.002).Conclusion Mutations in KDM6A are closely associated with prognosis and the immune microenvironment in BLCA,suggesting that KDM6A mutations may serve as potential therapeutic targets for BLCA.