Abstract Introduction: Gastric cancer remains a major cause of global cancer mortality and disproportionately affects underserved racial and ethnic minority populations in the United States. Latino patients experience a higher incidence and worse outcomes, yet genomic data and patient-derived models remain underrepresented. Whole-exome sequencing (WES) of our Latino GC cohort showed that 30% of tumors harbor pathogenic ARID1A mutations, paralleling TCGA frequencies. ARID1A, a core subunit of the SWI/SNF chromatin-remodeling complex, regulates enhancer activity and transcriptional accessibility. Its loss is linked to poor prognosis and metastasis. We hypothesized that ARID1A loss establishes an early premalignant state through chromatin dysregulation and transcriptional reprogramming. To test this, we developed long-term gastric organoid models derived from Latino patients to define the earliest cellular and molecular consequences of ARID1A loss. Methods: We generated multiple isogenic gastric organoid lines using CRISPR/Cas9 editing in Latino patient-derived normal gastric organoids, including ARID1A/TP53 double-knockout (dKO) organoids and TP53 knockout controls. Organoids were cultured long-term for up to 350 days, with early (∼150-day) and late (∼350-day) time points analyzed. Multi-omic characterization included H Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 670.
Arana et al. (Fri,) studied this question.