Harvard Reports on Cancer Prevention
Volume I: Human Causes of Cancer
Cancer Causes & Control:
An International Journal of Studies of Cancer in Human Populations
Official Journal of the International Association of Cancer Registries
Volume 7 Supplement November 1996 ISSN 0957-5243

Infectious Agents

Introduction
There is substantial evidence that infections are clearly or, in some cases, very likely causal factors in several types of cancer. These include surprisingly diverse types - most notably lymphoma as well as liver, nasopharynx, cervix, and stomach cancers. Although it has been known for decades that naturally acquired viral infections in animals could cause malignancy, the evidence in humans has accumulated more slowly.¹ With the advent of new molecular research tools, particularly those spawned from AIDS research, we now have strong evidence for the role of several viruses in human malignancy. In addition, there is accumulating evidence implicating infection with the Helicobacter pylori (a type of bacteria) in the occurrence of gastric cancer, and infection with Schistosoma haema tobium in the occurrence of cancer of the urinary bladder.

Latent and chronic infections
These infectious agents share in common the ability to either establish latency—that is, for the viral genes to persist in a subset of cells—following infection or to become chronic infections under certain conditions. An example of a latent infection is the Epstein-Barr virus (EBV), a member of the herpes family, which is transmitted primarily via saliva. Once infected, the EB viral genes persist in conjunction with the host DNA in a subset of white cells and in the upper part of the throat for the remainder of a person's life. Periodically, the virus will replicate, producing new viral particles which are neutralized by the immune response of the individual. Almost all adults have had an EBV infection and are thus carriers of these viral genes.² An example of a chronic infection is the hepatitis B virus (HBV), a less common infection transmitted by a variety of routes. Most HBV infections are cleared by an effective immune response. However with very early infection, such as from infected mother to child, or with very heavy exposure, such as with a contaminated blood transfusion, a chronic infection can be established. This can be detected by testing an individual's blood for the presence of the HB antigen.³

Secondary genetic damage
Another characteristic of several types of oncogenic infections is that risk of malignancy is related to the higher level of vi ral or bacterial replication than is usually seen, raising the probability of causing secondary genetic damage to the target tissues. This could be due to an early or severe primary infection or to a disruption of normal immune function leading to a change in the level of activation of a latent infection. An example of the effect of immune dysfunction is seen in HIV-1 infection, where many so-called opportunistic malignancies occur due to the loss of immunologic control of latent viral infections.⁴ Although these oncogenic infections tend to be quite prevalent (at least in some populations), the risk of subsequent malignancy is rare. Most carriers have no serious adverse effects. (An exception, of course, is HIV-I, which appears to be a new human infection.) And although all of these infectious agents are transmissible from person to person, any malignancy that may develop subsequently is not transmissible to another person. In addition to those noted above, the major oncogenic infectious agents include the hepatitis C virus (HCV), the human lymphotropic virus-type I (HTLV-I), and some of the subtypes of the human papilloma viruses (HPV).

It is now generally accepted that both HTLV-I and EBV are causal factors for several lymphomas. Specifically, HTLV-I is known to cause cancer of T-lymphocytes among adult carriers. Unlike most oncogenic viruses, HTLV-I is quite uncommon in most populations other than those in (or descended from) southern Japan, parts of central Africa, and islands in the South Pacific. This virus infection establishes latency in a subset of T-lymphocytes, and unlike HIV-I, no free HTLV-I virus is found in the non cellular component of the blood. Transmission occurs via contaminated blood exposure, from mother to child primarily by breast milk, and through prolonged sexual exposure to an infected partner. Risk of lymphoma in HTLV-I carriers is strongly related to very early infection.⁵ EBV is involved in the etiology of Burkitt's lymphoma—including almost all cases occurring among children in central Africa and about 20 percent of the cases elsewhere. With Burkitt's lymphoma, very early infection with EBV also appears to be important.² EBV is also clearly involved in about 35 percent to 50 percent of cases of Hodgkin's disease. This disease occurs most commonly in young adults, particularly those whose childhood social environment would foster susceptibility to late (post adolescent) infection with the EBV.⁶ Late infections with many so-called childhood infections, such as chicken pox or measles and including the EBV, can also be quite severe. In addition, EBV is implicated in the occurrence of nasopharyngeal carcinoma. In this tumor, ethnically related genetic factors are thought to be important because the disease is most common in persons of southern Chinese origin.⁷

Cancer of the liver can be caused by chronic infection with either HBV or HCV. Both viruses appear to act via chronic hepatitis, causing repeated cycles of cell death and regeneration. In these carriers, liver cancer usually occurs in the presence of cirrhosis. Chronic HBV infection is more common among Asian populations and among sub-Saharan Africans. In addition to blood and perinatal exposure, the virus can be transmitted from a chronic carrier to household members and less frequently to sexual partners. Intervention by immunization of infants at high risk—now underway in many populations in which the infection is prevalent—is likely to prevent the disease in future generations. Treatment of chronic HBV infection with a combination of drugs called interferons has been found to be effective sometimes.³ In contrast to the long history of research on HBV, HCV was not identified until 1989. It appears to be transmitted primarily by blood exposure. HCV is found worldwide with an overall prevalence of around one percent. Prevalence is somewhat higher in parts of Japan and other Asian populations, in the Middle East, and in parts of Africa. Not a lot is known about the course of HCV infection, but there is evidence that about a quarter of HCV carriers with chronic hepatitis can clear the infection with treatment by interferon a.³

HPV makes up a large family of at least 70 related strains that are highly adapted to infect various epithelial surfaces throughout the body. These viruses are extremely common and are transmitted primarily by direct contact. They cause benign warts and, in some cases, malignancy. The evidence linking several of the sexually transmitted types to cervical cancer is now established.⁸ In fact, tests to detect genes of these types are likely to become part of routine cervical screening.⁹ An important factor related to the development of cervical cancer includes a woman's own and her partners' history of sexual exposure. Further, the age at which a woman becomes sexually active plays a role, as risk is increased when a woman is exposed to the virus before full maturation of the cervix. Not surprisingly, these same genital HPV infections are also implicated in other anogenital cancers.⁸ It is likely that these and other subtypes also are involved in malignancy of other infected areas, including the oral cavity and upper respiratory tract.

Finally, recent findings strongly indicate that chronic H. pylori infection is involved in the development of gastric adenocarcinoma and some cases of gastric lymphoma.^10,11 The epidemiologic evidence that stomach cancer rates generally vary inversely with the level of economic development supports the role of early infection in pathogenesis.¹² Intervention trials have been undertaken to evaluate the effectiveness of eradicating the infection with antibiotics in high-risk populations.

Conclusion
The impact of these infections on the burden of cancer in the US is becoming increasingly evident because they are largely responsible for the cascade of opportunistic malignancies associated with AIDS. In global terms, the burden is heaviest among populations in developing countries, reflecting the impact of very early infection with these agents on subsequent risk of cancer. There are currently no vaccines available to prevent these chronic infections, other than for HBV. As a result, changes in behavior hold the most promise for prevention.

Table 1: The major oncogenic infections, their associated malignancies, and the estimated proportion of these malignancies attributed to the corresponding infections

Suggestions

Suggested Further Reading

References