These contain double-stranded DNA. A number of groups, the hepadana viruses (hepatitis B), papilloma viruses (HPV) and herpes viruses (EBV) are associated with hepatocellular carcinoma, uterine cervical cancer, Burkitt's lymphoma and nasopharyngeal carcinoma, respectively.
Liver cancer, the eighth commonest cancer worldwide, is particularly prevalent in sub-Saharan Africa, China, Japan and East Asia. Cholangiocarcinoma, although commonest in Asia (where it is associated with parasitic infections), does not present on the same scale as hepatocellular cancer which in China alone causes 100 000 deaths each year. More prevalent in males, 80% of cases develop in livers affected by multinodular cirrhosis.
Carriers of HbSAg have higher rates of both multinodular cirrhosis and hepatocellular carcinoma than non-carriers. Viral antigens have been identified in the liver cells of affected patients and the viral genome in cancer cells, suggesting that viral DNA may play a central role in the transforming process.
The exact mechanism underlying this process is unknown, but promotion by later exposure to mycotoxins (e.g. afla-toxin) or alcohol excess has been implicated. Unlike in the Western world, in which infection with HBV occurs through contact with blood and blood products or sexual activity (horizontal transmission), in the East it is transmitted vertically from mother to child during the first year of life. As 250 million humans worldwide are chronic carriers of the virus (10% of the population in some endemic areas), the scale of the problem is immense.
Eradicating HBV infection is obviously of huge importance. Large-scale programmes of vaccinating newborn infants, using a recombinant vaccinia virus carrying the HBV gene, are being evaluated. Exposure to aflatoxin is also being addressed.
HPV have small double-stranded circular genomes of DNA which cause benign infective skin warts. They infect basal cells during their proliferative phase which on full differentiation complete the life cycle of the virus. Genital warts, the third commonest form of sexually transmitted disease, are also due to infection by HPV, and are associated with carcinoma of the cervix. Some 30% of all women are infected with HPV and DNA sequences from this have been identified in the majority of cervical carcinomas. Over 70 types of HPV are known to infect genital sites but only a few (predominately types 16 and 18) are associated with neoplasia. Cofactors are smoking, infection by herpes simplex virus and, possibly, oral contraceptives.
Burkitt's lymphoma and nasopharyngeal cancer
EBV is a member of the herpes virus group. Its primary human target is the B-cell lymphocyte in which it establishes a latent infection. It may also infect cells of the nasopharynx, the parotid gland and the uterine cervix and is present in saliva and cervical secretions. Person-to-person spread by saliva during adolescence (e.g. by kissing) is probably the most important method of transmission in the West. In Africa and Asia, infection occurs during the first year of life causing a non-specific fever. The associated neoplasms, Burkitt's lymphoma and nasopharyngeal carcinoma, are uncommon in the Western world.
Burkitt's lymphoma first presented as a maxillary tumour, initially believed to be a localized granuloma or round-cell sarcoma, but with recognition that deposits were present also in kidneys, adrenals and ovaries, the condition was identified as an unusual form of lymphoma. The tumour occurs only in a belt north and south of the equator where there is a high rainfall and very high levels of malarial infections. The discovery of EBV in cells cultured from Burkitt's lymphoma suggested that this was the causative agent, but the disease can occur in its absence. Furthermore, EBV infection affects >95% of the world population. The restricted geographical distribution of Burkitt's lymphoma implicates a cofactor and this is believed to be constant antigen stimulation from malarial infection stimulating the continuous recruitment of new B-cells which, under the influence of virus, avoid programmed cell death.
Nasopharyngeal cancer, an undifferentiated epithelial cancer of the nasopharynx, is common in southern China, Hong Kong and amongst the Chinese in South-East Asia. EBV DNA can be detected in most tumour samples. Its restricted geographical distribution again indicates the importance of cofactors which are believed to be related to smoking and a diet of salt-cured fish and preserved meats rich in nitrosamines.
Certain types of cancer are more likely to occur in immuno-suppressed patients, indicating a protective role of the immune system against tumour formation. Immuno-suppressed patients following organ transplantation are more susceptible to lymphomas, Kaposi's sarcoma, and in the female, cancer of the cervix. Infection by the HIV types 1 and 2 has similar effects.
In AIDS patients, Kaposi's sarcoma occurs 20 000 times more frequently than in the general (HIV seronegative) population. The initial stimulus for transformation is a specific viral protein (tat) to which is added cell proliferative factors (cytokines) released from activated T-cells and possibly from the Kaposi cells themselves. As the risk of Kaposi's sarcoma is greater in those infected by AIDS as a result of sexual rather than other forms of contact, an additional sexually transmitted agent may be a cofactor.
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