The origin of oncogenic mutations: where is the primary damage?

Cancer is generally believed to arise from a single cell which has become ' initiated' by mutation of a few crucial genes, caused by random 'hits' in i ts DNA, a 'hit' being an error in DNA replication or a reaction of the :DNA with free radicals or other chemical species of exogenous or endogenous or igin. It is not obvious how the epidemiological data on cancer incidence ca n be interpreted within the framework of this paradigm. For example, it can not account quantitatively for the age dependence of cancer incidence, or f or the fact that the incidence of cancer in people with hereditary mutation s in tumour suppressor genes is much lower than expected, or for the observ ation that while in some types of cancer, like colon and pancreas, certain highly oncogenic mutations, such as that of TP53, are prevalent, there is n o significant increase in the incidence of these cancers in people who carr y the mutations by heredity. It is argued here that although mutations in s uch genes appear to be of crucial importance in carcinogenesis they may not be the rate limiting events in common cancer. The epidemiological data are consistent with the hypothesis that the rate limiting processes involve la rge numbers of cells. Conceivably, the mutations directly underlying neopla stic transformation may be the result of a local collapse in the system of intercellular processes on which the stability of the normal genotype and p henotype depends, and thereby trigger a cascade of mutations, among them th e highly oncogenic ones. This local collapse may be due to mutations of man y different genes in many cells as well as to other factors affecting the i ntegrity of tissue.