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

<div>Abstract<p>Intestinal metaplasia (IM) represents a precancerous condition associated with an increased risk of gastric cancer. A better understanding of whether and how precancerous lesions progress to gastric cancer is crucial for patient stratification and personalized prevention. In this study, we reconstruct evolutionary trajectories of genomic alterations in 330 multiregion matched samples of IM and tumors from 93 patients with gastric cancer. Intestinal-type gastric cancer (IGC) exhibited a higher mutation burden than diffuse-type gastric cancer (DGC), notably in genomically stable patients. IM from genomically stable patients carried more mutations associated with alcohol consumption. The 20 significantly mutated genes identified were classified into three evolutionary patterns. “Maintained” genes (<i>TP53</i>, <i>APC</i>, and <i>PIK3CA</i>) were commonly altered in IM and matched gastric cancer samples in both IGC and DGC, whereas <i>CDH1</i> mutations were specific to DGC. “Maintained” mutations in IM accelerated gastric cancer progression. Alterations in “IM-favored” genes (<i>MUC6</i>, <i>CFTR</i>, <i>BMP6</i>, and <i>MTRR</i>) were associated with IM development but were negatively selected in gastric cancer. Interestingly, <i>MUC6</i> mutations were enriched in specific pit cells with upregulation of <i>GKN1</i> and <i>GKN2</i>. The remaining genes were “gastric cancer–favored” and showed high heterogeneity in gastric cancer. These findings illuminate the genomic evolution from IM to IGC or DGC, providing insights that could guide precancerous lesion surveillance and early prevention strategies.</p>Significance:<p>Comprehensive genomic characterization uncovers maintained and gained alterations during evolution from intestinal metaplasia to gastric cancer, which could serve as predictive biomarkers to identify individuals at high risk of developing cancer.</p></div>