CANCER PREVENTION INSTITUTE OF CANADA

Last updated: 15-Jan-2007

Overview of Agents and Disease Burden

As noted above, several viruses, bacteria and even microscopic parasites are involved in the development of cancer in humans. A couple of features are shared by these agents. First, they are often highly prevalent in populations, whereas malignancies in infected people are much rarer. For example, half the world’s population harbours Helicobacter pylori, but only 1% develops gastric cancer.[1] Second, there is a prolonged latency period between initial infection and cancer development, during which time the agent persists in the host. Taken together, these facts suggest that cancers linked to infections follow the general pattern of most cancers, i.e., they are multi-factorial. In other words, infections are usually not sufficient for carcinogenesis; co-factors are required to promote both initiation and progression. One such factor, host genetic susceptibility, represents a particularly intense area of research.

Many synergies between infectious agents and other “environmental” factors are also being discovered; the latter include tobacco use, alcohol consumption and specific dietary components. Different infectious agents seem to interact with each other to create an additive or even multiplicative effect in terms of disease onset and progress. Human immunodeficiency virus type 1 (HIV-1) shows this effect with a number of other pathogens; another example is hepatitis B and C, which interact synergistically in the development of liver cancer.[2]

Some of these characteristics—prevalence in the general population, long latency, the role of other interacting factors—make the identification of causal relationships difficult. The etiology, or the causation, of disease is a notoriously complex area of medicine. When an agent is detected in tumours, there is no guarantee that it produced the cancer. Confirmation of an etiologic link requires a combination of epidemiological data, biological plausibility, and demonstrations of cellular proliferation in animal-based or in vitro studies. The ongoing work of confirming causation is reflected in the disparate inventories of cancer-linked infections provided in the appendices; because of political-legal implications, some government agencies are more “conservative” in adding agents to their list, as compared with the more expansive conclusions that may be drawn by academics and, especially, advocacy groups.

A final complicating factor in causation studies involves teasing apart the many subtypes of the carcinogenic viruses. For example, there are over 100 genotypes seen in human papillomavirus, but only a subset of these show a high risk for cancer development.[3]

The Cancers: Burden and Trends

The cancers with a significant infectious origin are not marginal. For example, stomach cancer, associated with the bacteria Helicobacter pylori, is the fourth most frequent cancer in the world, with 876,000 new cases in the year 2000. Liver cancer, with its strong association with the hepatitis viruses, is the fifth most common cancer globally and one of the leading causes of cancer death. Cervical cancer, with its well-known connection to the human papillomavirus, is the second most common type (after breast cancer) among women worldwide.[4] Augmenting the basic prevalence statistics is the fact that each of these cancers exhibit high rates of morbidity and mortality.

Although some key infection-linked cancers, such as Hodgkin’s disease and gastric and cervical cancer, show continuing decline in incidence in Canada, we cannot afford to be complacent. The reality is that, often due to a growing and, mostly, ageing population,[5] the absolute numbers and / or mortality burdens of some relevant cancers (e.g., non-Hodgkin’s lymphoma) continue to climb across the country and throughout the developed world. Disease latency also affects the trend-lines, increasing the impact over time of a disease such as cervical cancers (which tends to be diagnosed at a relatively young age); thus, even though cervical cancer rates are down, mortality attributable to this cancer is actually up in Canada.[6] In sum, the cancers associated with infections represent the loss of thousands of human lives. Thus, to quote international authorities, there is no question that “these specific oncogenic infections should be identified, monitored, and treated when indicated.”[7]

Geographical Variation of Disease

A complicating feature of global public health policies related to infection-based cancers is the wide variation in prevalence of the agent and / or the cancer, especially comparing developed and developing countries. For example, almost two-thirds of stomach cancer cases occur in the developing world, and cervical cancer follows a similar pattern. Likewise, only about 20% of liver cancer cases occur in the industrialized world, and they account for only 1% of total cancer cases in, for example, North America (compared to, for instance, 50% of cancer cases in China); however, the extremely high mortality rate with liver cancer somewhat mitigates any comfort among developed nations that may be derived from such statistics. Epidemiological studies confirm that the pattern of liver cancer can be largely explained by the worldwide distribution of chronic hepatitis infection, especially hepatitis B.[8]

One of the most obvious geographical variations relates to the third class of infectious agent (alongside viruses and bacteria), namely, parasitic worms or flukes. These organisms are almost entirely restricted to areas outside of North America (see the fuller description in a later section).

There are more localized variations in cancer rates which are also significant; for instance, the rate of liver cancer is high in Japan compared to other developed countries. Somewhat rarer cancers also swing more towards developed countries. For reasons that are not entirely clear, the highest incidence rate for non-Hodgkin’s lymphomas is observed in the developed areas of North America; the epidemiology cannot be entirely accounted for by the distribution of the major contributing agents, i.e., the Epstein-Barr and human immunodeficiency viruses.[9]Similarly, it is not yet clear if the somewhat higher leukemia rate in North America bears any connection to the pattern of infection with human T cell lymphotrophic virus type I.

Rates also vary within countries and provinces. The following two charts show the different incidence rates across Canada for stomach and cervical cancers.[10]

Epidemiology of the Main Infectious Agents in Developed Countries

The following table summarizes the major role of infection in carcinogenesis as seen in developed countries.

Other Agents Under Investigation

Before turning to our treatment of the confirmed infectious agents of interest in the developed world, it is important to note that this whole topic is a scientific “moving target.” First, several additional suspect agents are under investigation from all three classes of infection. For example, people chronically infected with Salmonella (the bacterium that causes typhoid) are up to 8 times more likely to develop gallbladder cancer.[24],[25] Various Helicobacter species have also garnered a lot of attention. For instance, Helicobacter bilis appears to play a role in biliary tract cancer.[26] Turning to the virus world, there is some evidence linking breast cancer to a human homologue of the mouse mammary tumour virus, as well as to cytomegalovirus.[27],[28] As noted in the table above, human herpesvirus type 8 has been identified as a probable cause of Kaposi sarcoma.

Second, the list of cancers related to already well-known agents is being lengthened all the time. For example, mucosa-associated lymphoid tissue (MALT) and other lymphomas of the stomach have been associated with Helicobacter pylori.[29],[30] This bacterium has also recently been connected to liver cancer[31] and biliary tract cancer.[32] As for viruses, hepatitis B and C also have been linked to biliary tract cancer,[33] and hepatitis C to non-Hodgkin’s lymphoma.[34] Human papillomavirus has been connected to breast cancer, as has Epstein-Barr virus; the latter also has been associated with lung, gastric, colon and prostate cancers.[35],[36] As will be described below, human papillomavirus has been detected in a spectrum of cancers as well.

The subtypes of specific viral agents being implicated in cancer development are steadily expanding as well. For example, the list of HPV subtypes demonstrated to cause cancer of the cervix gets longer and longer. Of the known subtypes of HPV, 15-20 have now been associated with cervical cancer.

Mechanisms of Disease

There are three main mechanisms by which infections both initiate and promote carcinogenesis:[37]

1. When an agent becomes persistent in the host, it may induce a chronic inflammatory response, which in turn creates a chemical environment damaging to the DNA and to other elements within cells (such as systems which regulate cellular growth and death); the proliferation of cells, a common precursor to malignancy, can be a by-product of these processes. Bacterial toxins can also directly damage DNA.

2. Agents may directly transform cells by inserting active genes into the host DNA; this can result in an interruption of cellular controls which normally inhibit cancerous growth. The insertion of DNA in a sperm or egg cell creates the possibility of viruses essentially being inherited by offspring.

3. Agents such as the human immunodeficiency virus (HIV) act as immunosuppressors, which create a climate conducive to aggressive cancer development.

Prevention and Management

Focusing on the main pathogens in developed countries, we will look at each one in turn from the point of view of effective health care. The agenda is to identify and evaluate the interventions available at various stages of exposure and disease development, namely:

1. Preventing exposure to the pathogen in the first place.

2. Preventing establishment of infection (e.g., through prophylactic vaccination).

3. Preventing full cancer development once infection is present (including detecting and treating the infection or precancerous cells and lesions before cancer becomes completely established, e.g., through therapeutic vaccination).

The first category is a form of early primary prevention. Category 2 measures, such as vaccinations, are classic forms of primary prevention. Finally, screening for precancer or early cancer and other approaches covered under category 3 are species of secondary prevention. The ultimate aim of all these approaches is clear, namely, preventing cancer from fully developing.

Future Developments

As already noted, there are many potentially carcinogenic agents being investigated. Likewise, tremendous research energy is going into the development of therapies for current and emerging infectious agents related to cancer. The key factor in making real progress on prevention and treatments is a full understanding of the mechanisms of transmission, infection and disease progression. As will be seen for each of the main agents described in the balance of this report, there is still a long way to go in understanding the basic science. As one review summarized:

At present, information concerning the role of viruses in the pathogenesis of human neoplasms is fragmented and incomplete. It is clear that their role is complex, and a complete understanding of the intricacies involved in viral interaction with the human genome may still take many years. New virologic study techniques can be expected to emerge and epidemiologic studies will continue. With each new report, a bit more will be understood, new hypotheses stimulated, and additional studies undertaken.[38]

[2] Donato F, Boffetta P, Puoti M. A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma. International Journal of Cancer. 1998; 75(3): 347-54.

[3] Munoz N, Bosch FX, de Sanjose S et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. New England Journal of Medicine. 2003; 348(6): 518-27.

[4] Parkin DM. International variation. Oncogene. 2004; 23(38): 6329-40.

[5] For example, stomach cancer is largely a disease of older age. Age-specific incidence and mortality rates do not begin to rise until age 40, and like many cancers, rates increase steeply only after age 50 (note: in Ireland, recent statistics showed that only about 1% of stomach cancer cases were in patients below age 35). These demographic factors explain why the incidence burden (total number of cases) of stomach cancer showed no percentage change for men in Canada over 1992-2001, even though the rate of stomach cancer has steadily declined.

[6] Canadian Cancer Society. Canadian Cancer Statistics 2005.

[7] Herrera LA, Benitez-Bribiesca L, Mohar A et al. Role of infectious diseases in human carcinogenesis. Environmental & Molecular Mutagenesis. 2005; 45(2-3): 284-303.

[8] Bosch FX, Ribes J, Cleries R et al. Epidemiology of hepatocellular carcinoma. Clinical Liver Diseases. 2005; 9(2): 191-211.

[9] Parkin DM. International variation. Oncogene. 2004; 23(38): 6329-40.

[10] Canadian Cancer Society. Canadian Cancer Statistics 2005.

[11] Evidence-based Cancer Prevention Strategies for NGOs. International Union Against Cancer; 2004.

[12] Pisani P, Parkin DM, Munoz N et al. Cancer and infection: estimates of the attributable fraction in 1990. Cancer Epidemiology, Biomarkers & Prevention. 1997; 6(6): 387-400.

[13] Walboomers JM, Jacobs MV, Manos MM et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. Journal of Pathology. 1999; 189(1): 12-9.

[14] Zhang J, Zou S, Giulivi A. Viral hepatitis and emerging blood borne pathogens in

Canada: Hepatitis B in Canada.2002. Available at http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/01vol27/27s3/27s3e_e.html. Accessed May 2005.

[15] Colditz GA, Atwood KA, Emmons K et al. Harvard report on cancer prevention volume 4: Harvard Cancer Risk Index. Risk Index Working Group, Harvard Center for Cancer Prevention. Cancer Causes & Control. 2000; 11(6): 477-88.

[16] Bosch FX, Ribes J, Diaz M et al. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004; 127(5 Suppl 1): S5-S16.

[17] Targeting Cancer: An Action Plan for Cancer Prevention and Detection. Cancer 2020 Background Report. Cancer Care Ontario; 2003.

[18] Huang JQ, Sridhar S, Chen Y et al. Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology. 1998; 114(6): 1169-79.

[19] Parkin DM. International variation. Oncogene. 2004; 23(38): 6329-40.

[20] Herrera LA, Benitez-Bribiesca L, Mohar A et al. Role of infectious diseases in human carcinogenesis. Environmental & Molecular Mutagenesis. 2005; 45(2-3): 284-303.

[21] McLoughlin RM, Sebastian SS, O'Connor HJ et al. Review article: test and treat or test and scope for Helicobacter pylori infection. Any change in gastric cancer prevention? Alimentary Pharmacology & Therapeutics. 2003; 17 Suppl 2: 82-8.

[22] Rickinson AB, Callan MF, Annels NE. T-cell memory: lessons from Epstein-Barr virus infection in man. Philosophical Transactions of the Royal Society of London - Series B: Biological Sciences. 2000; 355(1395): 391-400.

[23] Pisani P, Parkin DM, Munoz N et al. Cancer and infection: estimates of the attributable fraction in 1990. Cancer Epidemiology, Biomarkers & Prevention. 1997; 6(6): 387-400.

[24] Shukla VK, Singh H, Pandey M et al. Carcinoma of the gallbladder--is it a sequel of typhoid? Digestive Diseases & Sciences. 2000; 45(5): 900-3.

[25] Sheth S, Bedford A, Chopra S. Primary gallbladder cancer: recognition of risk factors and the role of prophylactic cholecystectomy. American Journal of Gastroenterology. 2000; 95(6): 1402-10.

[26] Murata H, Tsuji S, Tsujii M et al. Helicobacter bilis infection in biliary tract cancer. Alimentary Pharmacology & Therapeutics. 2004; 20 Suppl 1: 90-4.

[27] Levine PH, Pogo BG, Klouj A et al. Increasing evidence for a human breast carcinoma virus with geographic differences. Cancer. 2004; 101(4): 721-6.

[28] Richardson AK, Cox B, McCredie MR et al. Cytomegalovirus, Epstein-Barr virus and risk of breast cancer before age 40 years: a case-control study. Brirish Journal of Cancer. 2004; 90(11): 2149-52.

[29] Konturek PC, Konturek SJ, Starzyska T et al. Helicobacter pylori-gastrin link in MALT lymphoma. Alimentary Pharmacology & Therapeutics. 2000; 14(10): 1311-8.

[30] Parsonnet J, Hansen S, Rodriguez L et al. Helicobacter pylori infection and gastric lymphoma. New England Journal of Medicine. 1994; 330(18): 1267-71.

[31] Ito K, Nakamura M, Toda G et al. Potential role of Helicobacter pylori in hepatocarcinogenesis. International Journal of Molecular Medicine. 2004; 13(2): 221-7.

[32] Bulajic M, Maisonneuve P, Schneider-Brachert W et al. Helicobacter pylori and the risk of benign and malignant biliary tract disease. Cancer. 2002; 95(9): 1946-53.

[33] Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Seminars in Liver Disease. 2004; 24(2): 115-25.

[34] Matsuo K, Kusano A, Sugumar A et al. Effect of hepatitis C virus infection on the risk of non-Hodgkin's lymphoma: a meta-analysis of epidemiological studies. Cancer Science. 2004; 95(9): 745-52.

[35] Liu Y, Klimberg VS, Andrews NR et al. Human papillomavirus DNA is present in a subset of unselected breast cancers. Journal of Human Virology. 2001; 4(6): 329-34.

[36] Grinstein S, Preciado MV, Gattuso P et al. Demonstration of Epstein-Barr virus in carcinomas of various sites. Cancer Research. 2002; 62(17): 4876-8.

[37] Kuper H, Adami HO, Trichopoulos D. Infections as a major preventable cause of human cancer. Journal of Internal Medicine. 2000; 248(3): 171-83.

[38] Phelan JA. Viruses and neoplastic growth. Dental Clinics of North America. 2003; 47(3): 533-43.