Olnes, Matthew J.

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.

Abstract Gastric cancer is a leading cancer health disparity among the Alaska Native (AN) people, occurring at a 3-fold higher incidence and 4-fold higher mortality rate in comparison to U.S. Non-Hispanic whites (NHW). AN gastric cancer patients have significant differences in tumor location and appearance compared to NHW patients. In addition, AN patients are younger at the time of diagnosis, 60 versus 69 years and have a lower 5-year survival rate of 10% compared to 22% of NHW gastric cancer patients. The purpose of this research was to understand the role of gene mutations, inflammation, and infection as possible factors in the promotion of gastric cancer in the AN population. In this study, we examined previously obtained tissue samples from AN gastric cancer patients diagnosed between 2006-2014 at the Alaska Native Medical Center. Using next-generation sequencing, immunohistochemistry and in situ hybridization, we evaluated for 50 cancer related gene mutations, the presence of the virus, Epstein-Barr virus (EBV), the bacterium, Helicobacter pylori (H. pylori), and inflammatory factors. Cancer related gene mutations were observed in 69% of gastric tumors from AN patients. The most commonly mutated genes were TP53 (30%), PIK3CA (13%), STK11 (6%), KRAS (5%), and PTEN (5%). Of particular interest, gene mutations were associated with patients who were younger at time of diagnosis (less than 55 years old) and had a history of chronic gastritis. Additionally, EBV is associated with 23% of AN gastric cancers, which is significantly higher than the 10% of EBV associated gastric cancer cases observed in other populations. EBV associated AN gastric cancer patients were more likely to have a history of chronic gastritis, prior or current H. pylori infection, and tobacco use. Notably, aberrant overexpression of the inflammatory factor cyclooxygenase 2 (COX-2) and the glycoprotein Mucin 1 (MUC1) in gastric cancer cells was significantly associated with a poorer prognosis among AN gastric cancer patients. Collectively, these findings indicate infection and inflammation are potential driving factors in the pathogenesis of gastric cancer among the AN people, which may have important clinical implications. Citation Format: Holly Martinson, Steven Alberts, Matthew Olnes. Infection, inflammation and cancer: Understanding Alaska Native cancer health disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4239.

Abstract Gastric cancer in the Alaska Native (AN) people occurs at a 3-fold higher incidence and 4-fold higher mortality rate compared to Non-Hispanic Whites (NHW), representing one of the largest cancer disparities in the AN population. We aimed to review the AN gastric cancer burden and identify clinicopathological factors that are associated with cancer outcomes. Patient information was collected from 132 AN gastric cancer patients diagnosed between 2006-2015 at the Alaska Native Medical Center. The Surveillance, Epidemiology and End Result database 18 was used to collect comparison United States NHW gastric cancer patient data. Compared to NHW patients, AN gastric cancer patients have a higher incidence rate, are significantly younger, 60 versus 69 years, and have a poorer 5-year overall survival rate of 10% compared to 22%. AN patients differ from NHW patients in gastric cancer anatomic location, subtype, and higher presence of signet ring cell carcinomas. Forty-one percent of AN patients were positive at the time of diagnosis for Helicobacter pylori, 77% had chronic gastritis, 30% had a family history of a first-degree relative with gastrointestinal cancers, and 82% were current or former tobacco users. Using univariate analysis, diminished overall survival was observed with anatomic site, increasing stage, no treatment, the number of lymph nodes examined during resection, blood type, and chronic gastritis. Multivariable analysis revealed stage and treatment type were independently associated with improved overall survival. AN gastric cancer cases vary in their clinical and epidemiologic features, relative to NHW. Citation Format: Holly Martinson, Steven Alberts, Matthew Olnes. Gastric cancer in Alaska Native people: A cancer health disparity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5284. doi:10.1158/1538-7445.AM2017-5284