FIGURE 5.

Schematic illustration of the natural history of very well-differentiated gastric adenocarcinoma of intestinal type. RHOA mutation, CLDN18::ARHGAP fusion, and ARID1A loss are early events because they are present in the intramucosal low-grade components. TP53 mutation/p53 alteration is the major secondary event significantly associated with high-grade or diffuse-type transformation. Decreased E-cadherin expression is also associated with diffuse-type transformation. Tumor with mixed mucin phenotype is more likely to develop high-grade or diffuse-type transformation. Our analysis of the G17E/Y42C ratio suggested that diffuse-type gastric cancer more frequently develops from precursors other than very well-differentiated gastric adenocarcinoma. MM indicates muscularis mucosae.