Molecular evolution of intestinal-type early gastric cancer according to Correa cascade

Early screening is crucial for the prevention of intestinal-type gastric cancer. The current study aimed to ascertain the molecular evolution of intestinal-type gastric cancer based on the Correa cascade for precise gastric cancer screening. We collected sequential lesions of the Correa cascade in the formalin-fixed and paraffin-embedded endoscopic submucosal dissection (ESD)-resected specimens from 14 Chinese patients by microdissection, and subsequently determined the profiles of somatic aberrations during gastric carcinogenesis using whole-exome sequencing, identifying multiple variants at different Correa stages. The results showed that TP53, PCLO, and PRKDC were the most frequently mutated genes in early gastric cancer (EGC). We found a high frequency of TP53 alterations in low-grade intraepithelial neoplasia (LGIN), which further increased in high-grade intraepithelial neoplasia (HGIN) and EGC. Intestinal metaplasia (IM) showed no significant correlation with EGC in terms of mutational spectra, whereas both LGIN and HGIN showed higher genomic similarities to EGC, compared with IM. Based on Jaccard similarity coefficients, we constructed three evolutionary models, with most patients showing linear progression from LGIN to HGIN, ultimately resulting in EGC. The extracellular matrix-receptor interaction pathway was revealed to be involved in the linear evolution. Additionally, the retrospective validation study of 39 patients diagnosed with LGIN indicated that PRKDC mutations, in addition to TP53 mutations, may drive LGIN progression to HGIN or EGC. In conclusion, the current study unveils the genomic evolution across the Correa cascade of intestinal-type gastric cancer, elucidates the underlying molecular mechanisms of gastric carcinogenesis, and provides evidence for potential personalized gastric cancer surveillance.