Integrative Analysis of ATAC-Seq and Whole-Transcriptome Sequencing in the Trilogy of Gastric Carcinogenesis: From Normal Mucosa to Precancerous Lesions and to Gastric Cancer

Abstract

Background:Many specific biomarkers and target genes of gastric cancer have been identified, but the research areas on the characterization of epigenetic and transcriptional landscape in the process of gastric carcinogenesis, known as the trilogy from normal mucosa to precancerous lesions and finally to gastric cancer, remains a black box.Results:We performed whole-transcriptome sequencing and ATAC-seq based on human gastric tumours (T), gastric precancerous lesions (P) and normal gastric mucosa (N) and obtained chromatin open regions, circRNAs, lncRNAs, miRNAs, and mRNAs. Subsequently, differential expression analysis was performed on the N, P, and T groups, followed by GO, KEGG, and PPI analyses to investigate cancer-related hub genes (e.g., VEGFA, FN1, CDK1, and MYC) and extracellular matrix related signalling pathways that might serve as potential therapeutic targets in precancerous lesions and early gastric cancer. A core competing endogenous RNA (ceRNA) network was then constructed that contained 17 mRNAs, 11 miRNAs, 11 lncRNAs and two circRNAs, and the RNAs were validated by TCGA database and RT-PCR to prove they play crucial roles in the trilogy of gastric carcinogenesis; notably, hsa-miR-1226-5p, hsa-miR-6720-5p, lncRNA H19, ARID3A and GPR161 were significantly enriched in the complex network, which might be specificity tumour markers. Finally, ROC curve analysis suggested that nine mRNAs and five lncRNAs may be novel biomarkers with clinical implications for the precise diagnosis of early gastric cancer. Survivorship curve analysis further identified four mRNAs and one lncRNA as potential prognostic indicators. Conclusions:These results reveal a panel of premalignant and malignant specific marker genes in the trilogy of gastric carcinogenesis, potentially aiding the early identification of precancerous lesions and early gastric cancer. Meanwhile, the present study identifies the key molecular targets in the dynamic process of gastric carcinogenesis for experimental research on drugs and molecular mechanisms.