Gastric cancer is the fourth most common cancer and the second most common cause of cancer death worldwide, killing nearly 700,000 people each year. The most common histology is the intestinal (well-differentiated) type, which follows a temporal sequence of pathologic changes that leads from chronic non-atrophic gastritis, to atrophic gastritis, intestinal metaplasia, dysplasia, and finally gastric adenocarcinoma. Environmental factors such as excessive dietary salt and lack of fresh fruits and vegetables were long suspected to be the inciting event that initiated the gastric inflammatory response. However, our understanding of gastric cancer underwent a dramatic change with the discovery of Helicobacter pylori in 1982 by Marshall and Warren, who in 2005 were awarded the Nobel Prize in Physiology or Medicine. Approximately half the world's population is infected with H. pylori, with prevalence reaching more than 80% in many developing countries. While diet and host genetics continue to be recognized as important determinants of gastric cancer, approximately 60% of gastric cancer is attributable to H. pylori infection, prompting the designation of H. pylori as a carcinogen by the WHO. Early detection and preventive strategies offer the best opportunity to decrease mortality from gastric cancer, which is most commonly detected at stage III or IV where 5- year survival is only 3-13%. Identification of serum biomarkers for the histologic stages leading to gastric cancer offers the possibility for non-invasive detection of those H. pylori-infected patients who are most at risk for development of cancer. We hypothesize that a panel of protein or glycosylation biomarkers can be measured in serum that will permit early detection of precancerous lesions and guide intervention before the development of late stage cancer. We propose four Specific Aims: (1) Establish sets of serum samples from groups of patients with well-characterized precancerous or cancerous gastric histopathology; (2) Perform quantitative detection of protein biomarkers in serum of patients with well-characterized gastric histopathology using flow cytometric, multiplex immunoassays; (3) Perform mass spectrometry to identify oligosaccharide markers in serum from patients with well- characterized precancerous or cancerous gastric histopathology; and (4) Purify mucin glycoproteins from serum of patients with well-characterize gastric histopathology, and analyze O-linked glycans by MS. PUBLIC HEALTH RELEVANCE: Helicobacter pylori-associated gastric cancer is the second most common cause of cancer death in the world. We propose to identify serum biomarkers of gastric cancer and its precursor lesions that would permit early detection and intervention before the disease has progressed to an advanced stage where it is rarely curable.