Inadequate Caretaker Gene Function and Human Cancer Development

Both genetic and environmental factors have been implicated in the pathogenesis of human cancers. Yet for certain cancers, genetic factors act as critical contributors, while for other cancers, environmental factors seem to predominate in cancer causation. With the completion of the human genome project and accompanying advances in genomic technologies, genetic descriptions of inherited cancer risk and genetic signatures of cancer development are becoming increasingly refined. Already, it is clear that germline inheritance of certain mutant genes markedly increases cancer risks independent of environmental exposures. For example, inherited mutations in Rb , encoding a master cell-cycle regulatory gene, leads to the development of retinoblastoma, an otherwise rare cancer of the eye in children (1 ,2 ). In genomic DNA from retinoblastoma cells, the inherited mutant Rb alleles are typically accompanied by somatic alterations affecting the wild-type allele, resulting in a complete absence of normal Rb function in the cancer cells (3 ,4 ). Mice carrying targeted disruptions in Rb are also prone to develop cancers, supporting the notion that Rb functions as a tumor suppressor gene (5 ,6 ). Exposure to environmental carcinogens also markedly increases cancer risks. For example, cigarette smoke promotes the development of lung cancer, bladder cancer, and other cancers in a dose-dependent manner (7 ). Polycyclic aromatic hydrocarbons, as well as other compounds found in cigarette smoke, also promote cancer development in laboratory animal models, supporting the designation of such compounds as carcinogens (8 ,9 ).