Gastric cancer rates vary markedly with geography. The incidence is up to 20 times higher in Japan, Chile, Costa Rica, and Eastern Europe than in North America, northern Europe, Africa, and Southeast Asia. Mass endoscopic screening programs have been successful in regions of high incidence, such as Japan, where 35% of newly detected cases are early gastric cancer (i.e., tumors limited to the mucosa and submucosa). Unfortunately, mass screening programs are not cost-effective in regions in which the incidence is low, and less than 20% of cases are detected at an early stage in North America and northern Europe.
Gastric cancer is more common in lower socioeconomic groups and in individuals with multifocal mucosal atrophy and intestinal metaplasia. PUD does not impart an increased risk for development of gastric cancer, but patients who have had partial gastrectomies for PUD have a slightly higher risk for developing cancer in the residual gastric stump as a result of hypochlorhydria, bile reflux, and chronic gastritis.
In the United States, gastric cancer rates have dropped by more than 85% during the 20th century. Similar declines have been reported in many other Western countries, reflecting the importance of environmental and dietary factors. Despite this decrease in overall gastric adenocarcinoma incidence, cancer of the gastric cardia is on the rise. This trend probably is related to increased rates of Barrett esophagus and may reflect the growing prevalence of obesity and chronic GERD.
Gastric cancers are genetically heterogeneous, but certain molecular alterations are common. We will consider these first to be followed by the role of H. pylori–induced chronic inflammation and the association of a subset of gastric cancers with EBV infection.
• Mutations. While the majority of gastric cancers are not hereditary, mutations identified in familial gastric cancer have provided important insights into the mechanisms of carcinogenesis in sporadic cases. Germ line mutations in CDH1, which encodes E-cadherin, a protein that contributes to epithelial intercellular adhesion, are associated with familial gastric cancers, usually of the diffuse type. By comparison, mutations in CDH1 are present in about 50% of sporadic diffuse gastric tumors, while E-cadherin expression is drastically decreased in the rest, often by methylation of the CDH1 promoter. Thus, the loss of E-cadherin function seems to be a key step in the development of diffuse gastric cancer.
In contrast to CDH1, patients with FAP who have germ line mutations in adenomatous polyposis coli (APC) genes have an increased risk for development of intestinal-type gastric cancer. Sporadic intestinal-type gastric cancer is associated with several genetic abnormalities including acquired mutations of β-catenin, a protein that binds to both E-cadherin and APC protein; microsatellite instability; and hypermethylation of genes including TGFβRII, BAX, IGFRII, and p16/INK4a. TP53 mutations are present in a majority of sporadic gastric cancers of both histologic types.
H. pylori. Chronic gastritis, most commonly due to H. pylori infection, promotes the development and progression of cancers that may be induced by diverse genetic alterations (Chapter 6). As is the case with many forms of chronic inflammation, H. pylori–induced chronic gastritis is associated with increased production of proinflammatory proteins, such as interleukin-1β (IL-1β) and tumor necrosis factor (TNF). It is therefore not surprising that polymorphisms of genes that encode such factors and enhance production of these cytokines confer increased risk for development of chronic gastritis-associated gastric cancer in those with coexisting H. pylori infection.