Rate-limiting steps in carcinogenesis and their bearing on the incidence/age data for cutaneous melanoma and hepatocellular carcinoma

We analyze published data on cancer incidence as a function of age for (i) cutaneous melanoma for cohorts of males in Connecticut and (ii) hepatocellular cancer in Mozambique, China and Romania, on the basis of multi-hit models for carcinogenesis. The simple multi-hit model suggests an unlikely scenario in which, as the cohorts advance or the intensity of mutagenesis increases, fewer mutations are required to bring about the appearance of cancer. We present a new version of the multi-hit model in which two sets of mutatable loci are present, of differing sensitivities to mutagens. This provides a more acceptable description in which the number of rate-limiting steps for the appearance of cancer drops as the frequency of mutation rises, so that some of these steps are no longer rate-limiting.