Hispanic/Latino Patients with Gastric Adenocarcinoma Have Distinct Molecular Profiles Including a High Rate of Germline <i>CDH1</i> Variants.

Abstract

Hispanic/Latino patients have a higher incidence of gastric cancer and worse cancer-related outcomes compared with patients of other backgrounds. Whether there is a molecular basis for these disparities is unknown, as very few Hispanic/Latino patients have been included in previous studies. To determine the genomic landscape of gastric cancer in Hispanic/Latino patients, we performed whole-exome sequencing (WES) and RNA sequencing on tumor samples from 57 patients; germline analysis was conducted on 83 patients. The results were compared with data from Asian and White patients published by The Cancer Genome Atlas. Hispanic/Latino patients had a significantly larger proportion of genomically stable subtype tumors compared with Asian and White patients (65% vs. 21% vs. 20%, <i>P</i> < 0.001). Transcriptomic analysis identified molecular signatures that were prognostic. Of the 43 Hispanic/Latino patients with diffuse-type cancer, 7 (16%) had germline variants in <i>CDH1</i>. Variant carriers were significantly younger than noncarriers (41 vs. 50 years, <i>P</i> < 0.05). <i>In silico</i> algorithms predicted five variants to be deleterious. For two variants that were predicted to be benign, <i>in vitro</i> modeling demonstrated that these mutations conferred increased migratory capability, suggesting pathogenicity. Hispanic/Latino patients with gastric cancer possess unique genomic landscapes, including a high rate of <i>CDH1</i> germline variants that may partially explain their aggressive clinical phenotypes. Individualized screening, genetic counseling, and treatment protocols based on patient ethnicity and race may be necessary. SIGNIFICANCE: Gastric cancer in Hispanic/Latino patients has unique genomic profiles that may contribute to the aggressive clinical phenotypes seen in these patients.