Oncogenes

Raab-Traub, N, Raab-Traub, Nancy

HPV and EBV are common infectious agents that persist after primary infection in a latent state with occasional shedding of virus. Therefore, one of the fundamental questions in the etiology of those cancers that are linked to infection with such ubiquitous viruses is why cancer develops in a few people when many are infected. Because only a small subset of infected people will develop specific cancers, it has been suggested that the presence of the viral genomes in the malignancies merely indicates a persistent or latent infection. However, if the viral infection was not an etiologic factor in the development of the specific cancers, then one would predict that the proportion of cancers that contained the viral genome would reflect the proportion of infected people and that the same cancers could develop in uninfected people. The sporadic detection from nonendemic areas of Burkitt's lymphoma without EBV initially suggested that EBV infection was not etiologic. However, the rate of incidence of BL in infected populations of children is disproportionately greater than the very low incidence in uninfected children, which suggests that EBV infection is an important contributing factor. Moreover, the development of EBV-induced lymphomas in the immunocompromised and the consistent detection of EBV in specific epithelial malignancies such as NPC suggest that EBV infection is essential in the induction of specific cancers. Similarly, the consistent detection of particular HPV types in certain types of cancer suggests that HPV is also an etiologic factor. There are several strikingly similar aspects of infection with HPV and EBV. In latent infection, both of the viral genomes persist as an extrachromosomal episome with an origin of replication that is activated by binding to a virally encoded polypeptide. The state of viral infection appears to be linked with the state of cellular differentiation such that latent infections are activated into a replicative state as the cells differentiate. Moreover, elevated levels of expression of the putative transforming genes are linked to transformation. However, perhaps most importantly, the malignancies are clonal with regard to the viral infection; HPV-associated malignancies have unique integrative events and EBV-associated malignancies have clonal episomal forms. This reveals that the specific cancers are clonal cellular proliferations that developed after viral infection. In vitro, the initially polyclonal cell lines produced by EBV infection rapidly evolve to oligoclonality or monoclonality. This could be due to a slightly faster rate of growth such that the progeny of one clone rapidly predominate.(ABSTRACT TRUNCATED AT 400 WORDS)