PIK3R1基因低甲基化在肺腺癌中的临床意义

Clinical significance of PIK3R1 gene hypomethylation inlung adenocarcinoma

目的:为早期筛查、获取有效诊治手段来提高肺腺癌(LUAD)患者的总体生存率,探索PIK3R1基因低甲基化指标对肺腺癌诊疗及预后判断的影响。方法:使用大型公共数据库:TCGA、GEO、GEPIA2、UALCAN、KaplanMeier Plotter、LinkedOmics和TIMER进行在线分析。在LUAD人群不同的临床特征亚组中构建单变量和多变量COX比例风险模型。结果:低表达的PIK3R1会导致LUAD患者的总生存期(OS)、首次进展后生存期(FP)和疾病进展后生存期(PPS)较差。性别、肿瘤分期、吸烟史、T分型、N分型和PIK3R1低表达是LUAD发病的危险因素,低表达的PIK3R1是LUAD的潜在独立危险因素。DNA甲基化分析显示,探针ID(包括cg01239651、cg24797508、cg16664523和cg25008444)的PIK3R1启动子内CpGs的低甲基化通过DNA甲基转移酶(DNMT1)降低PIK3R1的表达。ROC曲线分析显示,PIK3R1的甲基化和表达在LUAD的准确诊断中具有高灵敏度和特异度。免疫分析研究表明,PIK3R1低甲基化和表达与免疫细胞(B细胞、CD8+T细胞、CD4+T细胞、巨噬细胞、中性粒细胞和树突状细胞)浸润有关。此外,共表达基因(PGR、C5orf41、SCN7A、RBMS3、FAT4、RASSF2、A2M、ITGA8、FLI1和RECK)通常与PIK3R1具有相似的功能。结论:PIK3R1的低甲基化及表达可视为肺腺癌的一种特异性诊断生物标志物和独立的预后因素,并可以预测免疫治疗的有效性。

Objective:To improve the overall survival rate of LUAD patients through early screening and access to effective diagnosic and therapeutic tools,and to explore the impact of PIK3R1 gene hypomethylation on the diagnosis and prognosis of LUAD.Methods:Large public databases were used for analysis:TCGA,GEO,GEPIA2,UALCAN,Kaplan-Meier Plotter,LinkedOmics,and TIMER databases.Constructing univariate and multivariate COX proportional-hazards model in the clinical characteristics sub-groups of different LUAD populations.Results:The lower-expressed PIK3R1 significantly contributed to worse Overall Survival(OS),First Progression(FP)and Post Progression Survival(PPS)in LUAD patients.Subgroup for gender,tumor stage,smoking history,T classification,N classification and low expression of PIK3R1 were acting risk roles in LUAD.Lower expressed PIK3R1 was a potential independent risk factor in LUAD.DNA methylation analysis showed hypo-methylation of CpGs within the PIK3R1 promoter of the probe IDs(including cg01239651,cg24797508,cg16664523 and cg25008444)were significantly related to the low-expressed PIK3R1 through DNMT1.Receiver Operating Characteristic(ROC)curve analysis showed that PIK3R1 methylation and expression can be highly sensitive and specific in the accurate diagnosis of LUAD.Immunoassay study demonstrated that PIK3R1 hypomethylation and expression are associated with immune cells infiltration(B cells,CD8+T cells,CD4+T cells,macrophages,neutrophils and dendritic cells).Finally the co-expression of PGR,C5orf41,SCN7A,RBMS3,FAT4,RASSF2,A2M,ITGA8,FLI1 and RECK typically have similar functions with PIK3R1 were found.Conclusion:PIK3R1 hypomethylation and expression serve as a specifically diagnostic biomarker and independent prognostic factor that predicting immunotherapy effectiveness.