Although the association of DNA viruses causally with human cancer has been known for more than four decades, it is only within the last 15 years or so that a causative association between specific RNA viruses and human neoplasia has been elucidated. The viruses involved are the hepatitis C virus and two retroviruses, human immunodeficiency virus and human T cell lymphotropic virus. Literally millions of humans are infected at the present time with these three different virus types, and the prospects for control and prevention are not bright at the present time.
Hepatitis Viruses and Human Cancer—Hepatitis C
While hepatitis B infection has been known or at least suspected as a cause of chronic viral hep- atitis and HCC for nearly half a century, the nature of hepatitis C virus as a cause for the same two conditions has been reasonably understood only for the last decade. Prior to that time, pa- tients with chronic viral hepatitis who did not exhibit evidence of hepatitis A or B infection were classified as infected with non-A, non-B (NANB) hepatitis virus (cf. Purcell, 1994). Cloning and sequencing of the hepatitis C virus genome, reported in 1989 (Choo et al., 1989), allowed for accelerated progress in our understanding of the nature of this virus and the pathogenesis of its effects in the human. The virus is quite infectious, with more than 50% of exposed individuals developing chronic infection. However, infection occurs almost entirely by the parenteral route with the most common mode of transmission involving transfusions and/or parenteral contact with blood products (Heintges and Wands, 1997). The proportions of the modes of viral infec- tion are seen in Figure 12.20. Blood transfusion, illicit intravenous drug use, and similar high- risk behavior accounts for 90% of HCV infections. Prior to 1990, when blood testing for HCV
Figure 12.20 Risk factors associated with HCV infections in the human. (From Koff, 1998, with per- mission of the author and publisher.)
began nationally, the transmission from blood transfusions was probably proportionally much higher than seen in Figure 12.20 (Alter, 1997). Antibodies to viral proteins are indicative of viral infection. The prevalence of such antibodies in blood donors in the world is seen in Figure 12.21. Although very high levels of infection are noted in regions of Africa, the Ukraine, and Vietnam, other areas including western countries exhibit significant levels of infection in the general population. In Japan, where HCV infection in relation to HCC development has been investigated, the risk of HCC among HCV carriers was 30% for males between the ages of 45 and 64 years and 6% for females between the ages of 50 and 64 years (cf. Tanaka and Tsukuma,1999). These studies indicate that HCV carriers have an extremely high probability of develop- ing HCC, and their lifetime risk for this disease is comparable to or greater than the risk of HBV carriers. In addition to HCV infection as a cause of HCC, the virus has also been implicated in the pathogenesis of low-grade non-Hodgkin lymphomas, especially those producing extensive amounts of cryoglobulins, a specific form of immunoglobulin-like molecules (cf. Silvestri and Baccarani, 1997; Pozzato et al., 1996). HCV has been found in bone marrow and lymphoid cells of infected patients and may cause B-cell clonal expansion (Santini et al., 1998). Infections with both HBV and HCC have been found in patients with hepatocellular carcinoma, but usually rep- resenting a relatively small percentage of the total, 1.6% to 3% in two different series (Tanaka and Tsukuma, 1999; Hadziyannis et al., 1995).