Functional modeling and characterization of high frequency mutations associated with gastric cancer in US racial and ethnic minority populations

Abstract Gastric cancer (GC) is the 5th most common neoplasm and the 2nd most deadly cancer worldwide, with an estimated 783,000 deaths in 2018. Furthermore, Hispanic/Latino Americans continue to be underrepresented in GC genomic studies despite being twice as likely to be diagnosed with and die from GC compared to non-Hispanic whites (NHW). In order to address this pervasive health disparity, our lab has led efforts to characterize tumor biopsies from racial/ethnic minority cancer patients to inform more effective cancer treatment and advance precision medicine among these high-risk populations. We performed whole-exome sequencing of 31 GC patient tumors with more than 60% of the samples coming from minority patients. We identified higher somatic mutation frequencies in the ARID1A, BRCA2, and APC genes compared with the TCGA GC cohort, which is made up of mostly NHW patients. To better understand the role these genes play in cancer tumorigenesis among racial/ethnic minority GC patients, our lab has established a CRISPR/Cas9 genome-editing platform in minority patient-derived organoids (mPDOs). In this study, we utilized our platform to generate mPDO models of APC-TP53 double knockouts (dKO), ARID1A-TP53 dKO, and TP53-ARID1A-BRCA2 triple knockouts in organoid lines derived from normal gastric tissue. We developed medium to select for functional mutants following organoid cell electroporation that yielded near-complete selection for the desired gene knockouts, allowing us to generate isogenic mPDO lines modeling each gene KO combination. Our organoid models will provide a critical method to elucidate therapeutic sensitivity and resistance mechanisms in minority groups towards the ultimate goal of addressing GC health disparities in US racial/ethnic minorities. Citation Format: Alexa Morales Arana, Nicole B. Halmai, Hongyong Zhang, Paul Lott, Ana Estrada-Florez, Ted W. Toal, University of California Minority Patient-DerivedXenograft (PDX) Development and Trial (UCaMP) Cent, Luis G. Carvajal-Carmona. Functional modeling and characterization of high frequency mutations associated with gastric cancer in US racial and ethnic minority populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3066.