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Evolution of Cancer Genes as a Mutation-driven Process¹

McArdle Laboratory, University of Wisconsin, Madison, Wisconsin 53706

Cancer is primarily a somatic genetic disease resulting from the accumulation of several precancerous mutations in a cell lineage. The evolution of highly oncogenic retroviruses has been used as a model for the evolution of a cancer cell. The properties of intermediates between one set of replication-competent retrovirus and protooncogene progenitors and the homologous highly oncogenic retrovirus were analyzed to differentiate between selection-driven and mutation-driven models of this evolution. In this case and in some other cases where sufficient data are available, it appears that the intermediates in the evolution of highly oncogenic retroviruses are not transforming, indicating that they were not formed in a purely selection-driven process. Furthermore, analysis of retrovirus mutation rates indicates that there is a high rate of mutation in retrovirus replication such that the evolution of highly oncogenic retroviruses could be mutation-driven. Other evidence is mentioned suggesting that oncogenesis in general is at least partially mutation-driven, although mutational mechanisms are involved that are different from those involved in the evolution of highly oncogenic retroviruses.

¹ Dedicated to the memory of Dr. Elizabeth C. Miller, a great scientist and human being.

² American Cancer Society Research Professor. The work in this author's laboratory is supported by PHS Grants CA-07175 and CA-22443 from the National Cancer Institute.

Received 9/17/87. Revised 11/17/87. Accepted 12/22/87.

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