Gastric cancer, or cancer of the stomach, was once considered a single entity. Now, scientists divide this cancer into two main classes: gastric cardia cancer (cancer of the top inch of the stomach, where it meets the esophagus) and non-cardia gastric cancer (cancer in all other areas of the stomach).
According to NCI's Surveillance, Epidemiology, and End Results (SEER) Program, an estimated 21,600 people in the United States will be diagnosed with gastric cancer and 10,990 people will die of this cancer during 2013. Gastric cancer is the second most common cause of cancer-related deaths in the world, killing approximately 738,000 people in 2008. Gastric cancer is less common in the United States and other Western countries than in countries in Asia and South America.
Overall gastric cancer incidence is decreasing. However, this decline is mainly in the rates of non-cardia gastric cancer. Gastric cardia cancer, which was once very uncommon, has risen in incidence in recent decades.
Infection with H. pylori is the primary identified cause of gastric cancer. Other risk factors for gastric cancer include chronic gastritis; older age; male sex; a diet high in salted, smoked, or poorly preserved foods and low in fruits and vegetables; tobacco smoking; pernicious anemia; a history of stomach surgery for benign conditions; and a family history of stomach cancer.
H. pylori has different associations with the two main classes of gastric cancer. Whereas people infected with H. pylori have an increased risk of non-cardia gastric cancer, their risk of gastric cardia cancer is not increased and may even be decreased.
What evidence shows that H. pyloriinfection causes non-cardia gastric cancer?
Epidemiologic studies have shown that individuals infected with H. pylori have an increased risk of gastric adenocarcinoma.The risk increase appears to be restricted to non-cardia gastric cancer. For example, a 2001 combined analysis of 12 case–control studies of H. pylori and gastric cancer estimated that the risk of non-cardia gastric cancer was nearly six times higher for H. pylori-infected people than for uninfected people.
Additional evidence for an association between H. pylori infection and the risk of non-cardia gastric cancer comes from prospective cohort studies such as the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study in Finland. Comparing subjects who developed non-cardia gastric cancer with cancer-free control subjects, the researchers found that H. pylori-infected individuals had a nearly eightfold increased risk for non-cardia gastric cancer.
What is cagA-positive H. pylori and how does it affect the risk of gastric and esophageal cancers?
Some H. pylori bacteria use a needle-like appendage to inject a toxin produced by a gene called cytotoxin-associated gene A (cagA) into the junctions where cells of the stomach lining meet. This toxin (known as CagA) alters the structure of stomach cells and allows the bacteria to attach to them more easily. Long-term exposure to the toxin causes chronic inflammation. However, not all strains of H. pylori carry the cagA gene; those that do are classified as cagA-positive.
Epidemiologic evidence suggests that infection with cagA-positive strains is especially associated with an increased risk of non-cardia gastric cancer and with reduced risks of gastric cardia cancer and esophageal adenocarcinoma. For example, a meta-analysis of 16 case–control studies conducted around the world showed that individuals infected with cagA-positive H. pylori had twice the risk of non-cardia gastric cancer than individuals infected with cagA-negative H. pylori. Conversely, a case–control study conducted in Sweden found that people infected with cagA-positive H. pylori had a statistically significantly reduced risk of esophageal adenocarcinoma. Similarly, another case–control study conducted in the United States found that infection with cagA-positive H. pylori was associated with a reduced risk of esophageal adenocarcinoma and gastric cardia cancer combined, but that infection with cagA-negative strains was not associated with risk.
Recent research has suggested a potential mechanism by which CagA could contribute to gastric carcinogenesis. In three studies, infection with CagA-positive H. pylori was associated with inactivation of tumor suppressor proteins, including p53.