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Current Thoughts on the Viral Etiology of Certain Human Cancers: The Richard and Hinda Rosenthal Foundation Award Lecture

Laboratory of Tumor Cell Biology, National Cancer Institute, NIH, Bethesda, Maryland 20205

The study of retroviruses now has direct relevance to the understanding of tumorigenesis in humans. This came about through direct demonstration of retroviruses as etiological agents in certain human tumors and through the discovery of a set of cellular genes (onc genes) that may play important roles in normal and abnormal cell growth by their association with certain animal retroviruses.

Cellular onc genes are a group of evolutionarily conserved sequences which are homologous to the transforming genes (v-onc) of oncogenic retroviruses. Although their functions in normal cells are largely not known, the sequence homology between cellular onc genes and the transforming v-onc genes is consistent with the idea that neoplastic transformation may, in some cases, be due to abnormal expression of these genes. We have approached this problem by molecular cloning of the human c-onc genes, using these as probes to examine the levels of expression and possible modification of these genes in different neoplastic and normal cells, and by determining their precise locations on the human chromosomes to correlate with known chromosomal alterations in human tumors. Through these studies, we provided evidence for gene amplification and chromosomal translocation as two mechanisms for c-onc activation in tumor cells and implicated the c-myc gene in Burkitt's lymphomas.

Human T-cell leukemia virus is a family of related T-lymphotropic viruses isolated from humans. This is the first and thus far the only exogenous human retrovirus identified. A subgroup of this family, human T-cell leukemia virus I, is etiologically associated with a distinct subtype of mature T-cell cancer called adult T-cell leukemia-lymphoma. This association is borne out by extensive seroepidemiology which revealed several regions of the world, including Southwestern Japan, the Caribbean Islands, and Africa, to be endemic; by demonstration of viral sequences clonally integrated in the adult T-cell leukemia cells; and, more remarkably, by the capacity of the virus to transform normal human T-cells in culture and in effect reproduce in vitro some of the in vivo leukemogenic events. Other subgroups that are distantly related to human T-cell leukemia virus I have been obtained from a patient with T-cell hairy cell leukemia and patients with acquired immunodeficiency syndrome. The full disease spectrum of these viruses remains to be determined.

Received 2/ 3/84. Accepted 4/ 3/84.