SETD2在恶性胸膜间皮瘤中的表达与临床意义研究

Expression and clinical significance of SETD2 in maligant pleural mesothelioma

目的分析恶性胸膜间皮瘤(MPM)基因突变概况和高频突变基因的表达水平,筛选出影响MPM患者预后的关键分子和临床病理因素。方法于2020年3月,分别从癌症基因组图谱(TCGA)数据库和人类肿瘤相关基因表达汇编(GEO)数据库下载86例MPM组织的基因二代测序数据和89例MPM组织样本的基因芯片表达数据,收集相关体细胞突变信息及对应的临床病理资料。汇总TCGA数据库中组织样本基因突变概况并分析高频突变基因表达水平与MPM患者临床病理学特征、石棉接触史和预后的关系,筛选出与MPM预后显著相关的基因进行基因集富集分析(GSEA)。利用GEO数据库的芯片表达数据对筛选出的关键基因和临床病理特征进行生存分析和GSEA验证。结果 TCGA数据集中单核苷酸变异(SNV)频率最高的10个基因是BAP1、NF2、TP53、TTN、SETD2、LATS2、CCDC168、FAT4、PTCH1和ZNF469。野生型NF2、TP53、SETD2和CCDC168基因的高表达率高于突变型,差异均具有统计学意义(P<0.05)。TCGA数据集Cox多因素分析结果显示,上皮型(HR=0.425,95%CI:0.235~0.767,P<0.01)和SETD2低表达(HR=0.516,95%CI:0.307~0.868,P=0.011)MPM患者的死亡风险较低。GEO数据集生存分析验证发现,上皮型MPM患者生存时间更长,肉瘤型MPM患者生存时间最短(P<0.01)。TCGA和GEO数据集富集结果显示STED2可能与G2M细胞周期检查点、E2F靶标基因、MYC靶标基因、蛋白分泌、有丝分裂纺锤体、MTORC1通路、TGF-β通路、雄激素反应和紫外线反应等通路相关。结论 MPM伴随着以BAP1、NF2、TP53、TTN、SETD2和LATS2等基因为代表的较高频率的基因突变。SETD2表达水平和组织类型中的上皮型可能是影响MPM预后的因素。

Objective To analyze the gene mutation profile in malignant pleural mesothelioma(MPM)and investigate the expression of high-frequency mutant genes and its relationship with clinicopathological parameters.To screen out key genes and clinicopathologic factors related to the prognosis of MPM patients.Methods The second generation sequencing data,somatic mutation data and clinical pathological data of 86 MPM cases and gene chip expression data of 89 MPM cases were downloaded from the Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)in March 2020.Summarize the gene mutation profile of tissue samples in the TCGA database and analyze the relationship between the expression level of high-frequency mutation genes and the clinicopathological characteristics,asbestos exposure history and prognosis of MPM patients.The genes significantly related to MPM prognosis were screened out for gene set enrichment analysis(GSEA).Survival analysis and GSEA were performed for the selected key genes and clinicopathological features verification using the microarray expression data from the GEO database.Results The top 10 genes with highest single nucleotide variations frequencies were BAP1,NF2,TP53,TTN,SETD2,LATS2,CCDC168,FAT4,PTCH1 and ZNF469.The high expression rates of NF2,TP53,SETD2 and CCDC168 genes in wild type were higher than those of mutated type,and the differences were statistically significant(P<0.05).Cox multivariate analysis of TCGA data showed that MPM patients with epithelial type(HR=0.425,95%CI:0.235-0.767,P<0.01)and SETD2 low expression(HR=0.516,95%CI:0.307-0.868,P=0.011)had lower risk of death.The survival analysis of GEO data verified that patients with epithelial type MPM had longer survival time,while patients with sarcoma type MPM had shortest survival time(P<0.01).GSEA showed that SETD2 was involved in G2M checkpoint,E2F targets,MYC signaling pathways,protein secretion,mitotic spindle,MTORC1 pathway,TGF-βpathway,androgen response and uv response.Conclusion MPM is accompanied with higher frequency of gene mutations represented by BAP1,NF2,TP53,TTN,SETD2,LATS2 and so on.SETD2 expression level and epithelia type of MPM may be influential factors for MPM prognosis.