| Background: The mechanisms of gastric cancer occurrence and progression are complex,and current studies have found that epigenetics is crucial for gastric cancer development,and some studies have also shown that it plays an important role in the advanced progression of gastric cancer.In recent years,genomic and epigenomic analysis techniques have enabled the identification of various specific epigenetic alterations in gastric cancer,among which DNA methylation may be a potential diagnostic and prognostic marker for gastric cancer.Part 1Objectives:To explore the relationship between methylation of multiple genes and the risk of gastric carcinogenesis.Methods: The relationship between promoter methylation of several genes and gastric cancer was investigated by meta-analysis.Firstly,Pub Med,EMBASE,CNKI,Wan Fang,Cqvip,and Cochrane libraries were systematically searched since their establishment until May 2021,and the literature was screened according to inclusion and exclusion criteria.The incidence of DNA methylation in tumor and non-tumor tissues was compared by integrating data from related studies,and the relationship between DNA methylation and other relevant clinical features of gastric cancer was assessed.Odds ratios was estimated using 95%confidence intervals and forest plots were generated using fixed-effect or random-effect models.Results:(1)A total of 201 studies(141 papers)were included,screening 8 genes,38 for p16 gene,30 for CDH1 gene,35 for h MLH1 genes,27 for RUNX3 gene,19 for RASSF1 A gene,18 for MGMT gene,21 for DAPK gene and 13 for CHFR gene.(2)Eight genes in this study were significantly more frequently methylated in gastric cancer than the control samples.(3)The DNA methylation frequencies of p16,CDH1,RUNX3 and DAPK genes showed an increasing trend from normal gastric mucosal tissue-precancerous condition/lesions-gastric cancer tissue.Conclusion: This study reveals the importance of multi-gene promoter methylation status in gastric cancer,indicating that DNA methylation can be used as a potential epigenetic biomarker in gastric cancer,and may serve as a potential indicator for clinical molecular diagnosis of gastric cancer in the future.Part 2Objectives: Screening of prognosis-related methylated-differentially expressed genes(MDEGs)based on public databases to establish a new prognostic model for gastric cancer.Methods: MDEGs were screened by integrating and analyzing a transcriptomic dataset and a methylation microarray dataset associated with gastric cancer in the GEO database.Then,based on the transcriptomic data of gastric cancer in the TCGA database and the corresponding clinical information,MDEGs in the previous step were combined to identify MDEGs associated with survival by one-way Cox and LASSO regression analysis and construct a MDEGs-based prognostic model.Patients were categorized into two high-and low-risk groups based on the median risk score of the TCGA dataset.The accuracy of model predictions was verified using Kaplan-Meier curves and subject operating characteristic(ROC)analysis.Immune cell infiltration in the different risk groups was analyzed by the CIBERSORT algorithm;immune and stromal scores were calculated by the ESTIMATE algorithm.Immunotherapeutic response in the high/low risk group was predicted by tumor immune dysfunction and exclusion(TIDE)algorithms,and the sensitivity to chemotherapeutic agents in both groups was predicted by the "p RRophetic" package.Results:(1)Overall survival(OS)was significantly lower in the high-risk group compared with the low-risk group(P<0.001).(2)The results of the univariate and the multivariate analyses suggest that this risk-score model can be used as an independent predictor of OS(HR>1,P<0.001).(3)Enrichment analysis showed that gastric cancer patients in the high-risk group were mainly enriched in the pathways of complement and coagulation cascade,focal adhesions,and ECM-receptor interactions.(4)Significant differences(P<0.05)were found in the infiltration of resting CD4 memory T cells,monocytes,resting dendritic cells,and follicular helper T cells immune cells between the high-and low-risk groups.(5)Patients in the high-risk group showed high sensitivity to 31 promising chemotherapeutic agents(P<0.01),such as DMOG,Embelin,Imatinib,Temsirolimus,Erlotinib,etc.And patients in the low-risk group were more sensitive to 7 chemotherapeutic agents(Gefitinib,GSK.650394,Erlotinib,GW843682 X,Methotrexate,BIBW2992,SL.0101.1).(6)Compared with the low-risk group,the high-risk group was more sensitive to immunotherapy(P<0.05).Conclusion: The signature model based on 6 MDEGs constructed in this study can not only be used for prognosis prediction of gastric cancer,but also can be considered as a clinical prediction model for gastric cancer immunotherapy response or chemotherapy sensitivity... |
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