胸腺嘧啶DNA糖基化酶的泛癌景观及其在肺腺癌中的潜在作用OA

Objective To examine the expression patterns,prognostic relevance,and immune regula-tory functions of thymine DNA glycosylase(TDG)across a spectrum of cancer types,with a particular emphasis on its role in lung adenocarcinoma.Methods A comprehensive analysis was conducted using multiple bioinfor-matics databases to assess TDG expression levels in pan-cancer contexts,as well as its associations with prognosis and immune regulation.The expression and clinical relevance of TDG in lung adenocarcinoma were examined through online platforms such as UALCAN and BEST.Additionally,small interfering RNA targeting TDG was de-veloped,and cell biological function assays were performed to determine the impact of TDG on cell functionality in lung adenocarcinoma.The LinkedOmics database was used to analyze the genes related to TDG and target kina-ses in lung adenocarcinoma,and their correlations with tumor status.The PRISM database was utilized to examine the correlation between TDG expression and clinical treatment response in lung adenocarcinoma.Results TDG was markedly overexpressed in a variety of cancers,including lung adenocarcinoma,papillary renal cell carcino-ma,and gastric cancer(all P<0.001).It held potential as a prognostic biomarker for hepatocellular carcinoma,lung adenocarcinoma,and papillary renal cell carcinoma.The expression of TDG was intricately linked to immune cell infiltration and tumor heterogeneity.In the context of lung adenocarcinoma,the analysis using the TIMER al-gorithm revealed negative correlations between TDG expression and the infiltration levels of CD4+T cells,den-dritic cells,and B cells(all P<0.001).Furthermore,CIBERSORT analysis demonstrated that TDG expression was positively correlated with activated CD4+memory T cells(P<0.001),neutrophils(P<0.001),resting NK cells(P<0.001),resting mast cells(P<0.001),M1 macrophages(P<0.001),M0 macrophages(P=0.014),and naive B cells(P<0.001),while it was negatively correlated with regulatory T cells(P<0.001),monocytes(P<0.001),activated mast cells(P<0.001),and memory B cells(P<0.001).Addi-tionally,TDG expression was positively associated with tumor mutational burden(P<0.001),microsatellite in-stability(P=0.045),mutant-allele tumor heterogeneity(P=0.001),and tumor neoantigens(P<0.001)in lung adenocarcinoma.In lung adenocarcinoma,the expression of TDG was notably elevated in the tumor tissue compared with that in adjacent normal tissue(P<0.001).Male patients exhibited higher levels of TDG expres-sion than female patients(P=0.002),and smokers demonstrated higher TDG expression than non-smokers(P<0.001).Furthermore,TDG expression was correlated with smoking cessation duration(P=0.014).Positive cor-relations were observed for TDG expression with both clinical T stage(P=0.003)and distant metastasis(P=0.012),while a negative correlation was found with patient prognosis(P=0.030).Furthermore,TDG emerged as an independent prognostic factor for lung adenocarcinoma.In vitro experiments revealed that silencing TDG in-hibited the proliferation and migration of lung adenocarcinoma cells(both P<0.05).A correlation analysis be-tween TDG-related genes and target kinases revealed that in lung adenocarcinoma,genes encoding aurora kinase A,cyclin-dependent kinase 2 and other enzymes exhibited positive correlations with TDG expression(all P<0.001).Furthermore,TDG expression demonstrated positive correlations with functional states including the cell cycle,DNA damage,and DNA repair processes(all P<0.001).In addition,the expression of TDG was corre-lated with the efficacy of treatment in the first course in clinical patients(P=0.007).Specifically,TDG expres-sion levels were higher in the progressive disease group than in the stable disease group(P=0.016),and lower in the complete remission group than in the progressive disease group(P<0.001).Additionally,elevated TDG expression was associated with enhanced resistance to oxaliplatin(P<0.001),carmustine(P<0.001),and olaparib(P=0.004).Conclusion TDG serves as a potential prognostic biomarker,an immunotherapeutic tar-get,and a oncogene in pan-cancer,with particular significance in lung adenocarcinoma.