The multihit model of carcinogenesis: etiologic implications for colon cancer

A new multihit model of carcinogenesis is developed for use in evaluating age-specific cancer incidence rates in human populations. The model allows for some heterogeneity in both risk (perhaps genetic) and pathway (number of hits). Fitting the model yields estimates of (1) levels of effect of background exposure to environmental agents, (2) tumor growth times after initiation of a malignant cell, and (3) relative sizes of high-risk groups in a human population. Maximum likelihood procedures are used to fit the model to the polyposis coli data of Veale and the colon cancer incidence data from the Third National Cancer Survey. Model estimates may be verified in some cases by review of independent data in the literature and results have both theoretical and practical implications. Findings are generally consistent with the adenoma-carcinoma etiologic sequence postulated by Hill, Morson and Bussey with one exception. A large proportion of the population may be at risk of four-hit colon tumors following a non-adenoma etiologic sequence.