Gastric cancer (GC) is the second leading cause of cancer-related deaths worldwide. While overall incidence and mortality rates have dropped in recent decades, GC remains a significant cause of health disparities for many racial and ethnic minority groups in the US, including Hispanic/Latino Americans (HLAs). Despite a high minority cancer burden, few FDA-approved targeted therapies are available for GC. This can be partially explained by limited availability of cancer genome data and patient-derived models from racial/ethnic minority populations, hampering therapeutic target identification and drug efficacy studies. Our group has spearheaded the development of the University of California Minority Patient-Derived Xenograft Development and Trial Center (UCaMP) with the goal of addressing these critical issues for GC patient care. Thus far, we have characterized over 30 GC samples from racial/ethnic minorities with more than 60% of samples coming from HLAs. Genomic analyses have revealed a significantly higher prevalence of genomically stable GC (GS-GC) tumors among HLAs compared to TCGA, which is comprised of mostly NLWs. GS-GC is the most aggressive and treatment resistant of the four TCGA-defined molecular subtypes. While we have discovered genomic alterations in several therapeutically targetable pathways among our minority-patient GC tumors, GS-GC tumors remain largely devoid of targetable mutations. These observations have led us to assess the epigenome to inform therapeutic development. We performed reduced representation bisulfite sequencing on 15 GC tumor-adjacent normal pairs from our UCaMP cohort. We identified significantly hyper- and hypomethylated genes and performed overlaps with RNA expression data from TCGA stomach adenocarcinoma cases to identify epigenetically silenced and activated genes unique to each molecular subtype. For GS-GC samples, pathway enrichment analysis revealed significant enrichment of key cancer pathways among silenced genes for GS samples, including WNT/NOTCH, PI3K/Akt, focal adhesions and cell-extracellular matrix interactions, and pro-growth/anti-apoptotic signaling. Importantly, GS samples showed silencing of two PI3K/Akt pathway regulatory subunits, PIK3R2 and PIK3R5, suggesting aberrant signaling of this highly therapeutically targetable pathway despite lack of mutational alterations. This data has provided a basis for further testing of PI3K/Akt targeted inhibitors using our minority patient-derived organoid and xenograft models to treat GS-GC, a GC subtype for which there are currently few effective treatment options and is associated with significant health disparities for Hispanic/Latinos.

Citation Format: Nicole B. Halmai, Hongyong Zhang, Paul C. Lott, Ana Estrada-Florez, Ted W. Toal, Javier Torres, UCaMP Consortium, Luis G. Carvajal-Carmona. Characterizing the DNA methylome of gastric cancer among Hispanic/Latinos to advance cancer precision health equity [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C056.