Helicobacter pylori and Cancer
- Helicobacter pylori (H. pylori) is a type of bacterium that is found in the stomach of about two-thirds of the world’s population.
- H. pylori infection is a major cause of gastric (stomach) cancer, specifically non-cardia gastric cancer (cancer in all areas of the stomach, except for the top portion near where it joins the esophagus). H. pylori infection also causes gastric mucosa-associated lymphoid tissue (MALT) lymphoma.
- H. pylori infection is associated with a decreased risk of some other cancers, including gastric cardia cancer (cancer in the top portion of the stomach) and esophageal adenocarcinoma.
What is Helicobacter pylori?
To survive in the harsh, acidic environment of the stomach, H. pylori secretes an enzyme called urease, which converts the chemical urea to ammonia. The production of ammonia around H. pylori neutralizes the acidity of the stomach, making it more hospitable for the bacterium. In addition, the helical shape of H. pylori allows it to burrow into the mucus layer, which is less acidic than the inside space, or lumen, of the stomach. H. pylori can also attach to the cells that line the inner surface of the stomach.
Although immune cells that normally recognize and attack invading bacteria accumulate near sites of H. pylori infection, they are unable to reach the stomach lining. In addition, H. pylori has developed ways of interfering with local immune responses, making them ineffective in eliminating this bacterium (1, 2).
H. pylori has coexisted with humans for many thousands of years, and infection with this bacterium is common. The Centers for Disease Control and Prevention (CDC) estimates that approximately two-thirds of the world’s population harbors the bacterium, with infection rates much higher in developing countries than in developed nations.
Although H. pylori infection does not cause illness in most infected people, it is a major risk factor for peptic ulcer disease and is responsible for the majority of ulcers of the stomach and upper small intestine. More information about H. pylori and peptic ulcer disease is available from the National Institute of Diabetes and Digestive and Kidney Diseases.
In 1994, the International Agency for Research on Cancer classified H. pylori as a carcinogen, or cancer-causing agent, in humans, despite conflicting results at the time. Since then, it has been increasingly accepted that colonization of the stomach with H. pylori is an important cause of gastric cancer and of gastric mucosa-associated lymphoid tissue (MALT) lymphoma (see Questions 2–5,7,9). Infection with H. pylori is also associated with a reduced risk of esophageal adenocarcinoma (see Questions 4–6).
H. pylori is thought to spread through contaminated food and water and through direct mouth-to-mouth contact. In most populations, the bacterium is first acquired during childhood. Infection is more likely in children living in poverty, in crowded conditions, and in areas with poor sanitation.
What is gastric cancer?
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 (3). 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 (4). Gastric cardia cancer, which was once very uncommon, has risen in incidence in recent decades (5).
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 (6, 7).
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. pylori infection causes non-cardia gastric cancer?
Epidemiologic studies have shown that individuals infected with H. pylori have an increased risk of gastric adenocarcinoma (1,2,8–12). 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 (8).
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 (13). 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 (14).
What is the evidence that H. pylori infection may reduce the risk of some cancers?
Several studies have detected an inverse relationship between H. pylori infection and gastric cardia cancer (14–16), although the evidence is not entirely consistent (17, 18). The possibility of an inverse relationship between the bacterium and gastric cardia cancer is supported by the corresponding decrease in H. pylori infection rates in Western countries during the past century—the result of improved hygiene and widespread antibiotic use—and the increase in rates of gastric cardia cancer in these same regions.
Similar epidemiologic evidence suggests that H. pylori infection may be associated with a lower risk of esophageal adenocarcinoma. For example, a large case–control study in Sweden showed that the risk of esophageal adenocarcinoma in H. pylori-infected individuals was one-third that of uninfected individuals (15). A meta-analysis of 13 studies, including the Swedish study, found a 45 percent reduction in risk of esophageal adenocarcinoma with H. pylori infection (19). Moreover, as with gastric cardia cancer, dramatic increases in esophageal adenocarcinoma rates in several Western countries parallel the declines in H. pylori infection rates.
How might H. pylori infection decrease the risk of some cancers but increase the risk of other cancers?
Although it is not known for certain how H. pylori infection increases the risk of non-cardia gastric cancer, some researchers speculate that the long-term presence of an inflammatory response predisposes cells in the stomach lining to become cancerous. This idea is supported by the finding that increased expression of a single cytokine (interleukin-1-beta) in the stomach of transgenic mice causes sporadic gastric inflammation and cancer (20). The increased cell turnover resulting from ongoing cellular damage could increase the likelihood that cells will develop harmful mutations.
One hypothesis that may explain reduced risks of gastric cardia cancer and esophageal adenocarcinoma in H. pylori-infected individuals relates to the decline in stomach acidity that is often seen after decades of H. pylori colonization. This decline would reduce acid reflux into the esophagus, a major risk factor for adenocarcinomas affecting the upper stomach and esophagus.
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 (21, 22). 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 (23). 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 (16). 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 (24).
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 (25–27).
What is gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and what is the evidence that it can be caused by H. pylori infection?
Gastric MALT lymphoma is a rare type of non-Hodgkin lymphoma that is characterized by the slow multiplication of B lymphocytes, a type of immune cell, in the stomach lining. This cancer represents approximately 12 percent of the extranodal (outside of lymph nodes) non-Hodgkin lymphoma that occurs among men and approximately 18 percent of extranodal non-Hodgkin lymphoma among women (28). During the period 1999–2003, the annual incidence of gastric MALT lymphoma in the United States was about one case for every 100,000 persons in the population.
Normally, the lining of the stomach lacks lymphoid (immune system) tissue, but development of this tissue is often stimulated in response to colonization of the lining by H. pylori (2). Only in rare cases does this tissue give rise to MALT lymphoma. However, nearly all patients with gastric MALT lymphoma show signs of H. pylori infection, and the risk of developing this tumor is more than six times higher in infected people than in uninfected people (29, 30).
Is H. pylori infection associated with any other cancer?
Whether H. pylori infection is associated with risk of other cancers remains unclear. Some studies have found a possible association between H. pylori infection and pancreatic cancer, but the evidence is conflicting (31, 32). Studies investigating the possibility that H. pylori is a risk factor for colorectal adenocarcinoma (33) or lung cancer (32, 34) have found no evidence that it is associated with the risk of either type of cancer.
Can treatment to eradicate H. pylori infection reduce gastric cancer rates?
Long-term follow-up of data from a randomized clinical trial carried out in Shandong, China—an area where rates of gastric cancer are very high—found that short-term treatment with antibiotics to eradicate H. pylori reduced the incidence of gastric cancer. During a nearly 15-year period after treatment, gastric cancer incidence was reduced by almost 40 percent (35). When the results of this trial were pooled with those of several smaller trials examining the effects on gastric cancer incidence of antimicrobial treatment to eradicate H. pylori, a similar reduction was seen (35).
Who should seek diagnosis and treatment of an H. pylori infection?
According to the Centers for Disease Control and Prevention (CDC), people who have active gastric or duodenal ulcers or a documented history of ulcers should be tested for H. pylori, and, if they are infected, should be treated. (More information is available from CDC.) Testing for and treating H. pylori infection is also recommended after resection of early gastric cancer and for low-grade gastric MALT lymphoma. However, most experts agree that the available evidence does not support widespread testing for and eradication of H. pylori infection (36).
Atherton JC. The pathogenesis of Helicobacter pylori-induced gastro-duodenal diseases. Annual Review of Pathology 2006; 1:63–96.[PubMed Abstract]
Kusters JG, van Vliet AH, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clinical Microbiology Reviews 2006; 19(3):449–490.[PubMed Abstract]
Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International Journal of Cancer 2010; 127(12):2893–2917.[PubMed Abstract]
Anderson WF, Camargo MC, Fraumeni JF, et al. Age-specific trends in incidence of noncardia gastric cancer in US adults. JAMA 2010; 303(17):1723–1728.[PubMed Abstract]
de Martel C, Forman D, Plummer M. Gastric cancer: Epidemiology and risk factors. Gastroenterology Clinics of North America 2013; 42(2):219-240.[PubMed Abstract]
Forman D, Burley VJ. Gastric cancer: Global pattern of the disease and an overview of environmental risk factors. Best Practice & Research Clinical Gastroenterology 2006; 20(4):633–649.[PubMed Abstract]
Brenner H, Rothenbacher D, Arndt V. Epidemiology of stomach cancer. Methods in Molecular Biology 2009; 472:467–477.[PubMed Abstract]
Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: A combined analysis of 12 case control studies nested within prospective cohorts. Gut 2001; 49(3):347–353.[PubMed Abstract]
Parsonnet J, Friedman GD, Vandersteen DP, et al. Helicobacter pylori infection and the risk of gastric carcinoma. New England Journal of Medicine 1991; 325(16):1127–1131.[PubMed Abstract]
Huang JQ, Sridhar S, Chen Y, Hunt RH. Meta-analysis of the relationship between Helicobacter pylori seropositivity and. Gastroenterology 1998; 114(6):1169–1179.[PubMed Abstract]
Eslick GD, Lim LL, Byles JE, Xia HH, Talley NJ. Association of Helicobacter pylori infection with gastric carcinoma: A meta-analysis. American Journal of Gastroenterology 1999; 94(9):2373–2379.[PubMed Abstract]
Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. New England Journal of Medicine 2001; 345(11):784–789.[PubMed Abstract]
The alpha-tocopherol, beta-carotene lung cancer prevention study: Design, methods, participant characteristics, and compliance. The ATBC Cancer Prevention Study Group. Annals of Epidemiology 1994; 4(1):1–10.[PubMed Abstract]
Kamangar F, Dawsey SM, Blaser MJ, et al. Opposing risks of gastric cardia and noncardia gastric adenocarcinomas associated with Helicobacter pylori seropositivity. Journal of the National Cancer Institute 2006; 98(20):1445–1452.[PubMed Abstract]
Hansen S, Melby KK, Aase S, Jellum E, Vollset SE. Helicobacter pylori infection and risk of cardia cancer and non-cardia gastric cancer. A nested case-control study. Scandinavian Journal of Gastroenterology 1999; 34(4):353–360.[PubMed Abstract]
Ye W, Held M, Lagergren J, et al. Helicobacter pylori infection and gastric atrophy: Risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia. Journal of the National Cancer Institute 2004; 96(5):388–396.[PubMed Abstract]
Kamangar F, Qiao YL, Blaser MJ, et al. Helicobacter pylori and oesophageal and gastric cancers in a prospective study in China. British Journal of Cancer 2007; 96(1):172–176.[PubMed Abstract]
Dawsey SM, Mark SD, Taylor PR, Limburg PJ. Gastric cancer and H pylori. Gut 2002; 51(3):457-458.[PubMed Abstract]
Islami F, Kamangar F. Helicobacter pylori and esophageal cancer risk: A meta-analysis. Cancer Prevention Research 2008; 1(5):329–338.[PubMed Abstract]
Tu S, Bhagat G, Cui G, et al. Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell 2008; 14(5):408–419.[PubMed Abstract]
Wen S, Moss SF. Helicobacter pylori virulence factors in gastric carcinogenesis. Cancer Letters 2009; 282(1):1–8.[PubMed Abstract]
Bagnoli F, Buti L, Tompkins L, Covacci A, Amieva MR. Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells. Proceedings of the National Academy of Science USA 2005; 102(45):16339–16344.[PubMed Abstract]
Huang JQ, Zheng GF, Sumanac K, Irvine EJ, Hunt RH. Meta-analysis of the relationship between cagA seropositivity and gastric cancer. Gastroenterology 2003; 125(6):1636–1644.[PubMed Abstract]
Chow WH, Blaser MJ, Blot WJ, et al. An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma. Cancer Research 1998; 58(4):588–590.[PubMed Abstract]
André AR, Ferreira MV, Mota RM, et al. Gastric adenocarcinoma and Helicobacter pylori: Correlation with p53 mutation and p27 immunoexpression. Cancer Epidemiology 2010; 34(5):618–625.[PubMed Abstract]
Wei J, Nagy TA, Vilgelm A, et al. Regulation of p53 tumor suppressor by Helicobacter pylori in gastric epithelial cells. Gastroenterology 2010; 139(4):1333–1343.[PubMed Abstract]
Tsang YH, Lamb A, Romero-Gallo J, et al. Helicobacter pylori CagA targets gastric tumor suppressor RUNX3 for proteasome-mediated degradation. Oncogene 2010; 29(41):5643–5650.[PubMed Abstract]
Wu XC, Andrews P, Chen VW, Groves FD. Incidence of extranodal non-Hodgkin lymphomas among whites, blacks, and Asians/Pacific Islanders in the United States: Anatomic site and histology differences. Cancer Epidemiology 2009; 33(5):337–346.[PubMed Abstract]
Parsonnet, J, Hansen S, Rodriguez L, et al. Helicobacter pylori infection and gastric lymphoma. New England Journal of Medicine 1994; 330(18):1267–1271.[PubMed Abstract]
Sagaert X, Van Cutsem E, De Hertogh G, Geboes K, Tousseyn T. Gastric MALT lymphoma: A model of chronic inflammation-induced tumor development. Nature Reviews Gastroenterology & Hepatology 2010; 7(6):336–346.[PubMed Abstract]
Stolzenberg-Solomon RZ, Blaser MJ, et al. Helicobacter pylori seropositivity as a risk factor for pancreatic cancer. Journal of the National Cancer Institute 2001; 93(12):937–941.[PubMed Abstract]
de Martel C, Llosa AE, Friedman GD, et al. Helicobacter pylori infection and development of pancreatic cancer. Cancer Epidemiology, Biomarkers and Prevention 2008; 17(5):1188–1194.[PubMed Abstract]
Limburg, PJ, Stolzenberg-Solomon RZ, Colbert LH, et al. Helicobacter pylori seropositivity and colorectal cancer risk: A prospective study of male smokers. Cancer Epidemiology, Biomarkers and Prevention 2002; 11(10 Pt 1):1095-1099.[PubMed Abstract]
Koshiol J, Flores R, Lam TK, et al. Helicobacter pylori seropositivity and risk of lung cancer. PLoS One 2012;7(2):e32106.[PubMed Abstract]
Ma JL, Zhang L, Brown LM, et al. Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality. Journal of the National Cancer Institute 2012; 104(6):488-492.[PubMed Abstract]
Kamangar F, Sheikhattari P, Mohebtash M. Helicobacter pylori and its effects on human health and disease. Archives of Iranian Medicine 2011; 14(3):192-199.[PubMed Abstract]
This text may be reproduced or reused freely. Please credit the National Cancer Institute as the source. Any graphics may be owned by the artist or publisher who created them, and permission may be needed for their reuse.