Genomic Analyses Reveal the Evolving Characteristics of Intestinal Metaplasia and Gastric Cancer

Abstract Intestinal metaplasia (IM) represents a precancerous condition associated with an increased gastric cancer (GC) risk. A better understanding of whether and how precancerous lesions progress to GC is crucial for patient stratification and personalized prevention. Here, we reconstruct evolutionary trajectories of genomic alterations in 330 multi-region matched samples of IM and tumors from 93 GC patients. Intestinal-type gastric cancer (IGC) exhibited a higher mutation burden than diffuse-type gastric cancer (DGC), notably in genomically stable (GS) patients. IM from GS patients carried more mutations associated with alcohol consumption. The 20 significantly mutated genes identified were classified into three evolutionary patterns. "Maintained" genes (TP53, APC, and PIK3CA) were commonly altered in IM and matched GC samples in both IGC and DGC, while CDH1 mutations were specific to DGC. "Maintained" mutations in IM accelerated GC progression. Alterations in "IM favored" genes (MUC6, CFTR, BMP6, and MTRR) were associated with IM development but were negatively selected in GC. Interestingly, MUC6 mutations were enriched in specific pit cells with upregulation of GKN1 and GKN2. The remaining genes were "GC favored" and showed high heterogeneity in GC. These findings illuminate the genomic evolution from IM to IGC or DGC, providing insights that could guide precancerous lesion surveillance and early prevention strategies.