子宫内膜样腺癌中TP53突变与预后和免疫应答的研究

Relationship between TP53 mutation and prognosis and immune response in endometrial adenocarcinoma

目的筛选子宫内膜样腺癌中关键突变基因,并研究其表达与免疫反应和预后的关系。方法从癌症基因组图谱(The Cancer Genome Atlas,TCGA)和基因型组织表达(Genotype-Tissue Expression,GTEx)下载全部543例子宫内膜样腺癌和177例正常组织数据,进行生物信息学分析。收集22例子宫内膜样腺癌手术样本,RT-qPCR验证基因表达。结果TCGA数据库中,超过96.38%的患者存在突变,其中错义突变、单核苷酸变异和C>T突变较多,突变基因排在前10位的分别为PTEN、PIK3CA、TTN、ARID1A、TP53、MUC16、PIK3R1、KMT2D、CTCF和CSMD3。TCGA中TP53突变型表达显著高于野生型(P<0.0001)。癌组织中TP53表达均高于正常组织,TP53突变型表达均高于野生型(P<0.05)。TP53突变型的总体生存期(Overall Survival,OS)、无进展生存期(Progression Free Survival,PFS)、无病生存期(Disease Free Survival,DFS)和疾病特异性生存期(Disease Free Survival,DSS)均低于TP53野生型(P<0.0001,P<0.0001,P=0.001,P<0.0001)。在野生型和突变型TP53中,共鉴定出344个差异性基因(上调195个,下调149个)。与野生型相比,突变型负富集在“免疫效应器进程”、“免疫应答”、“免疫系统进展”、“先天免疫应答”和“免疫应答调控”通路(P=0.001)。TP53突变型的T细胞CD8+、内皮细胞、巨噬细胞和非特征细胞评分低于野生型。结论子宫内膜样腺癌中TP53高表达,且突变型表达高于野生型。TP53突变与不良预后正相关,且能抑制免疫应答。

Objective To screen the key Mutation Genes in endometrial adenocarcinoma and study the relationship between their expression and immune response and prognosis.Methods The data of 543 cases of endometrial adenocarcinoma and 177 cases of normal tissues were downloaded from the Cancer Genome Atlas(TCGA)and genotype tissue expression(GTEX)for bioinformatics analysis.22 cases of endometrial adenocarcinoma were collected,RT-qPCR was used to verify the gene expression.Results More than 96.38%of the patients had mutations,including missense mutation,single nucleotide mutation and C>T mutation.The top 10 mutations were PTEN,PIK3CA,TTN,ARID1A,TP53,MUC16,PIK3R1,KMT2D,CTCF and CSMD3.In TCGA,the expression of TP53 mutant was significantly higher than that of wild type(P<0.0001).The expression of TP53 in cancer tissue was higher than that in normal tissue,and the expression of TP53 mutant was higher than that of wild type(P<0.05).The overall survival(OS),progression free survival(PFS),disease free survival(DFS)and disease free survival(DSS)of TP53 mutant were lower than those of TP53 wild type(P<0.0001,P<0.0001,P=0.001,P<0.0001).A total of 344 differentially expressed genes(195 up-regulated and 149 down regulated)were identified in wild-type and mutant TP53.Compared with the wild type,the mutant was negatively enriched in the"immune effector process","immune response","immune system progress","innate immune response"and"immune response regulation"pathways(P=0.001).The scores of T cell CD8+,neutrophil,macrophages and meyloid dendritic cells of TP53 mutant were lower than those of wild type.Conclusion TP53 is highly expressed in endometrioid adenocarcinoma,and the expression of mutant is higher than that of wild type.TP53 mutation is positively correlated with poor prognosis and can inhibit immune response.