Abstract PR005: Uncovering the Etiology of Early-Onset Gastric Cancer in Latinos Through Germline and Tumor Genomic Profiling

Abstract Gastric cancer (GC) is a leading cancer health disparity among U. S. Latinos and a major cause of cancer mortality across Latin America. The incidence of early-onset GC (diagnosed before age 50) is increasing, yet the causes of this rise remain unclear. Potential contributors include the obesity epidemic and microbiome dysbiosis, but data specific to Latino populations are limited. We conducted a comprehensive genomic study of Latino GC patients, including whole-exome germline sequencing from 500 individuals and somatic tumor profiling from over 200 cases. Most patients were diagnosed before age 50. This study aimed to investigate both genetic and non-genetic etiologies of GC in Latinos. Germline analyses revealed a high prevalence of pathogenic variants in intermediate- to high-penetrance cancer susceptibility genes. We also identified several novel candidate genes and found evidence supporting a role for mosaicism in disease development. Somatic analyses showed that 82% of early-onset tumors belonged to the genetically stable subtype, compared to 28% in TCGA data. Significant differences in driver mutation frequencies were observed between early- and late-onset cases. Early-onset tumors had higher mutation rates in CDH1 (24% vs. 14%), ZNF99 (16% vs. 7%), and ROCK1 (11% vs. 4%), and lower rates in PIK3CA (3% vs. 14%) and RHOA (0% vs. 12%). Additionally, a history of Helicobacter pylori infection was associated with increased tumor mutation burden (TMB) in early-onset patients (p=0. 023), but not in late-onset cases (p=0. 76), suggesting exposure to more aggressive bacterial strains or a distinct tumor microbiome. Ongoing analyses are focused on mutational signatures and tumor microbiome variation and will be presented at the meeting. Together, these findings reveal key molecular differences between early- and late-onset GC in Latinos and suggest that non-genetic factors may play a significant role in the etiology of early-onset disease in this population. Citation Format: Luis G. Carvajal-Carmona. Uncovering the Etiology of Early-Onset Gastric Cancer in Latinos Through Germline and Tumor Genomic Profiling. abstract. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31 (23Suppl): Abstract nr PR005.