Abstract
Gastric cancer is an aggressive and heterogeneous malignancy that often varies in presentation and disease among racial and ethnic groups. The Alaska Native (AN) people have the highest incidence and mortality rates of gastric cancer in North America. This study examines molecular markers in solid tumor samples from eighty-five AN gastric adenocarcinoma patients using next-generation sequencing, immunohistochemistry, and in situ hybridization analysis. AN patients have a low mutation burden with fewer somatic gene mutations in their tumors compared to other populations, with the most common mutation being TP53. Epstein-Barr virus (EBV) was associated with 20% of AN gastric cancers, which is higher than the world average of 10%. The inflammation marker, cyclooxygenase-2 (COX-2), is highly expressed in patients with the lowest survival rates. Mismatch repair deficiency was present in 10% of AN patients and was associated with patients who were female, 50 years or older, gene mutations, and tumors in the distal stomach. Program death-ligand 1 (PD-L1) was expressed in 14% of AN patients who were more likely to have MMR deficiency, EBV-associated gastric cancers, and mutations in the PIK3CA gene, all of which have been linked to clinical response to PD-1 inhibitors. These studies suggest a portion of AN gastric cancer patients could be candidates for immunotherapy. Overall, this study highlights future avenues of investigation for clinical and translational studies, so that we can improve early detection and develop more effective treatments for AN patients.
Highlights
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death worldwide [1]
We performed a retrospective analysis of 85 AN patients who had clinical biopsies or resection tissue samples taken for locally advanced gastric adenocarcinomas at the Alaska Native Medical Center
We investigated the incidence of Epstein-Barr virus (EBV) in AN gastric cancer patients and observed 20% of patient tumors were positive for the latent EBV marker EBV-encoded small ribonucleic acid 1 (EBER1), indicating that the AN population exhibits a higher percentage of EBV+ gastric cancer than most reported studies, and a rate comparable to a recently reported cohort of gastric cancer patients in
Summary
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death worldwide [1]. The prevalence of gastric cancer varies geographically, with the majority of Cancers 2020, 12, 198; doi:10.3390/cancers12010198 www.mdpi.com/journal/cancers. The majority of gastric cancer cases are adenocarcinomas, which are commonly subdivided into intestinal and diffuse types, according to Lauren classification [3]. Gastric cancer patients are often diagnosed at advanced stages because of the lack of screening strategies, leaving most patients with limited treatment options. There is an urgent need to better understand the pathogenesis of gastric cancer and to identify early detection and biomarkers that can be utilized to identify more effective and less toxic therapeutic strategies. The pathogenesis of gastric cancer is commonly associated with infectious agents such as Helicobacter pylori (H. pylori) [4] and Epstein-Barr virus (EBV) [5].
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