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1 An Historical Overview of Oncogenes

Harold Varmus


Medical science has been comfortable for at least a few decades with the general idea that cancer represents a fundamental disorder of cellular growth control, a disorder that arises in rare cells after birth through changes in genes or their expression, gives those cells a growth advantage over surrounding cells, and is inherited by daughter cells like a stable genetic trait. By these properties, cancer differs from the other large categories of disease to which vertebrates fall prey—infections that destroy tissues, degenerative disorders of aging, and inherited genetic deficiencies—even though cancer also can be caused by infection, occurs more often with advancing age, and sometimes depends on inherited mutations.

What has been much less clear until the past decade is the identity of the genes affected in a cancer cell and the nature of the changes. Many hypotheses have been advanced to account for the origins of cancer: e.g., that cancers result from genes introduced into somatic cells by viruses; that cancers depend on activation of viral genes that preexist in our germ lines as a consequence of ancient infections; that cancers arise upon inappropriate expression of cellular genes that are beneficial in other cell types, especially embryonic cells; and that cancers are caused by mutations (physical changes) in an important subset of our genes. The hypothetical viral or cellular genes that influence carcinogenesis have been proposed to control nuclear events (DNA replication and transcription), metabolic pathways, or cell-surface interactions that regulate growth.

Evaluation of such...

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