Hispanic/Latino Patients with Gastric Adenocarcinoma Have Distinct Molecular Profiles Including a High Rate of Germline CDH1 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%, P < 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 CDH1. Variant carriers were significantly younger than noncarriers (41 vs. 50 years, P < 0.05). In silico algorithms predicted five variants to be deleterious. For two variants that were predicted to be benign, in vitro 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 CDH1 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.

Figure 1.. Hispanic/Latino (Hs/L) gastric cancer patients are of unique ancestry as compared to Asian and White patients.

Principal component (PC) analysis was performed using Locating Ancestry from SEquence Reads (LASER) comparing Hispanic/Latino patients from this study to Asian and White patients analyzed by The Cancer Genome Atlas (TCGA). The Human Genome Diversity Project (HGDP) was used as the reference.

Figure 2.. Gastric cancer in Hispanic/Latino (Hs/L) patients are predominantly of the genomically stable subtype.

a. Tumors from 57 Hispanic/Latino gastric cancer patients were subtyped and listed by descending mutation burden. Clinical and molecular data are depicted. MB = megabase, WT = wild-type. b. Molecular classification of samples within each ethnicity/race. P < 0.001. EBV: Epstein-Barr virus infected, MSI: microsatellite instability, CIN: chromosomal instability, GS: genomically stable.

Figure 3.. Key genomic features of gastric cancer are identified in Hispanic/Latino (Hs/L) samples.

a. Recurrent somatic mutations identified by the TCGA in non-hypermutated gastric cancer samples from Hispanic/Latino patients. b. Structural variations seen in Hispanic/Latino gastric cancer samples. CIN: chromosomal instability, GS: genomically stable, WT: wild-type, *: CLDN18-ARHGAP45, all other fusions were CLDN18-ARHGAP26. c. Comparison of incidence of somatic alterations in select genes involved in RTK/RAS/PI(3)K signaling, cell cycle, cell adhesion, Wnt signaling, and chromatin remodeling, in the TCGA and Hs/L cohorts, stratified by CIN and GS subtypes.

Figure 4.. Transcriptomic signatures of gastric cancer from Hispanic/Latino patients are prognostic.

a. Unsupervised consensus clustering based on the top 50 most variably expressed genes. MSI: microsatellite instability, CIN: chromosomal instability, GS: genomically stable. b. Kaplan-Meier curves comparing overall survival based on clusters. P < 0.001. c. Normalized enrichment scores from Gene Set Enrichment Analysis (GSEA) comparing Cluster 1 to Clusters 2, 3, 4, and 5. Orange dots denote Hallmark gene sets related to cell cycle, cell growth, and epithelial-mesenchymal transition, all of which had false-discovery rate q-value < 0.01 d. Normalized enrichment scores from GSEA analysis comparing Cluster 4 to Clusters 1, 2, 3, and 5. Red dots denote immune-related Hallmark gene sets, all of which had false-discovery rate q-value < 0.01

Figure 5.. Hispanic/Latino gastric cancer patients have high rates of germline CDH1 mutations.

a. Seven germline CDH1 mutations were identified in patients with diffuse gastric cancer. b. Western blot showing E-cadherin expression level upon transfection of plasmids carrying wild-type CDH1, A286G variant, or G1849A variant into Chinese hamster ovary cells. c. Representative pictures of scratch assays. Distance between the wound edges were measured after 24 hours. d. Quantification of remaining distance between wound edges, relative to 0h. N ≥ 9 per group, with at least two independent experiments. ** P < 0.01, *** P < 0.001, **** P < 0.0001