Molecular characterization of Latino gastric adenocarcinomas identifies homologous recombination deficiency and TGF-beta pathways as targets for aggressive genomically stable tumors

Background: Gastric cancer (GC) disproportionately affects Latino populations, yet genomic data from these patients remain scarce. This underrepresentation limits understanding of ancestry-specific molecular features that could inform targeted therapies. Tumors characterized by a genomically stable (GS) subtype are associated with worse outcomes and is more prevalent among Asians and Hispanics than among non-Latino White (NLW) and Black populations. Methods: We analyzed 192 gastric adenocarcinoma tumors from Latino patients (Colombia, Mexico, and U.S.) using low-pass whole-genome sequencing (LP-WGS), or whole-exome sequencing. Molecular subtypes were classified, and somatic alterations were assessed and compared to the NLW cohort from the cancer genome atlas (TCGA). Results: Similar to previous studies, the GS subtype was predominant (57.8%) in this Latino cohort, significantly higher than the mostly NLW, TCGA-STAD (11.5%, p < 10⁻²⁹). GS tumors had frequent alterations in cadherin/catenin complex genes (CDH1, CTNND1) as well as the DNA damage repair gene ATM, and TGF-beta related pathway members TGFBR2 and ELF3. We identified six novel significantly mutated genes in non-hypermutated tumors and subtype-specific drivers that differ in frequency based on self-identified race. Comparative analysis revealed genetic ancestry-linked differences, including greater Indigenous American (IA) ancestry in diffuse histology tumors and higher CDH1 mutation frequency. Analysis of the therapeutically actionable biomarkers were limited in GS tumors (65% lacked targets), but ATM mutations suggest potential benefit from PARP inhibitors. Conclusions: Latino GC tumors are enriched for GS subtype and harbor unique genomic alterations, including novel drivers and HRR pathway defects. These findings underscore the need for ancestry-informed therapeutic strategies and highlight PARP inhibition as a promising avenue for GS tumors.