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Hispanic/Latino gastric adenocarcinoma patients have distinct molecular profiles including a high rate of germline CDH1 mutations

By Sam C. Wang, Yunku Yeu, Suntrea TG Hammer, Shu Xiao, Min Zhu, Changjin Hong, Lynn Y Yoon, Ibrahim Nassour, Jeanne Shen, Deepak Agarwal, Scott I Reznik, John C Mansour, Adam C Yopp, Hao Zhu, Tae Hyun Hwang, Matthew R Porembka

Posted 11 Sep 2019
bioRxiv DOI: 10.1101/764779 (published DOI: 10.1158/0008-5472.CAN-19-2918)

Hispanic/Latino patients have a higher incidence of gastric cancer and worse cancer-related outcomes as compared to patients of other backgrounds. Whether there is a molecular basis for these disparities is unknown, as very few Hispanic/Latino patients were included in previous studies. We performed a large, integrated genomic analysis of gastric cancer samples from Hispanic/Latino patients. Whole-exome sequencing (WES) and RNA sequencing were performed on 57 Hispanic/Latino gastric cancer patient samples. Germline analysis was conducted on 83 patients. Functional testing of CDH1 germline mutations was performed in Chinese hamster ovary cells. Tumors from Hispanic/Latino patients were significantly enriched for the genomically-stable subtype (as defined by The Cancer Genome Atlas), compared to Asians and Whites (65% vs 21% vs 20%, P < 0.001). Transcriptomic analysis identified molecular signatures that were prognostic. Of the 43 Hispanic/Latino patients with diffuse-type gastric cancer, 7 (16%) had germline mutations in CDH1 . Mutation carriers were significantly younger than non-carriers (41 vs 50 years, P < 0.05). E-cadherin expression was reduced in 5 of 6 mutation carrier tumor samples available for analysis. In silico algorithms predicted 5 variants were deleterious. For the two variants that were predicted to be benign, we demonstrated that the mutations conferred increased migratory capability, suggesting pathogenicity. Hispanic/Latino gastric cancer patients possess unique genomic landscapes. This includes a high rate of CDH1 germline mutations that may partially explain their aggressive clinical phenotypes. Individualized screening, genetic counseling, and treatment protocols based on patient ethnicity and race may be necessary.

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