Modeling early gastric cancer evolution following <i>ARID1A</i> loss in Latino patient-derived organoids.

Abstract

e16144 Background: Gastric cancer remains a leading cause of cancer mortality worldwide, with disproportionately worse outcomes among Latino patients in the United States. Despite this burden, Latino populations remain underrepresented in genomic datasets and preclinical models. ARID1A is one of the most frequently mutated tumor suppressor genes in gastric cancer, yet its role in early disease evolution remains incompletely understood. We sought to develop patient-derived gastric organoid models to understand how ARID1A loss contributes to early phenotypic progression. Methods: Normal gastric organoids were established from Latino patients and engineered using CRISPR/Cas9 to generate isogenic ARID1A/TP53 double-knockout (dKO) and TP53 knockout. Organoids were maintained in long-term culture for up to 350 days. Early (~150 days) and late (~350 days) time points were evaluated using histologic changes, RNA sequencing, and whole-exome sequencing to assess phenotypic progression and evolution. Functional assays evaluating proliferation, migration, and drug sensitivities are ongoing. Results: ARID1A/TP53 dKO organoids exhibited progressive morphological changes and increased proliferative features compared with wild-type controls. RNA sequencing demonstrated time-dependent changes, including suppression of digestion and iron transport pathways and upregulations associated with cilium movement and ciliogenesis. Whole exome sequencing revealed shared mutations across independently derived dKO clones, alongside acquisition of clone-specific variants over time. These alterations involved genes implicated in transcriptional regulation, extracellular matrix remodeling, and receptor signaling, consistent with early genomic instability and divergent clonal evolution. Conclusions: Patient-derived gastric organoids from Latino individuals demonstrate that combined ARID1A and TP53 loss drives transcriptional reprogramming and promotes early dysplastic progression. These models establish a translational platform to interrogate gastric cancer evolution and to identify therapeutic vulnerabilities associated with ARID1A loss. Collectively, these findings have implications for risk stratification, early detection, and precision prevention strategies in high-risk populations.