As a consequence of the analysis of the occurrence of retinoblastoma, Moolgavkar and Knudson (1981) proposed a two-stage model with clonal expansion of ''intermediate" cells for human carcinogenesis. The model has been shown to provide a qualitative description of the age-dependent incidence of all human cancers for both children and adults (Moolgavkar and Venzon 1979; Moolgavkar 1983) and has been applied to the epidemiology of carcinomas of the breast and lung (Stevens and Moolgavkar 1979; Moolgavkar and others 1979, 1980, 1989, 1993) and radon-induced lung tumors in rats (Moolgavkar and others 1990). The mathematical nature of the model has been investigated (Moolgavkar and others 1988; Moolgavkar and Luebeck 1990; Moolgavkar 1992; Heidenreich 1996; Heidenreich and others 1997, in press) The model, or slight modifications of it, is gaining increasing use for the analysis of radiation-induced cancer in both epidemiologic and animal studies (Kai and others 1993; Leenhouts and Chadwick 1994a,b, 1997; Little 1995; Venema and others 1995; Holt 1997; Moolgavkar 1997), although some workers continue to take the Armitage-Doll multistage model into account (Little and others 1992, 1994; Chen 1993; Little and Charles 1994; Little 1995, 1996).

THE TWO-MUTATION MODEL

Although the modifications of the two-mutation model lead to some quantitative differences in analyses, a global description that covers the essence of the model can be used to gain an insight into the cancer process and derive some generally applicable implications. A schematic representation of the two-mutation model based on the developments of Moolgavkar and Knudson (1981) is given in figure 5.



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