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 its 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 origin. It is not obvious how the epidemiological data on cancer incidence can be interpreted within the framework of this paradigm. For example, it cannot account quantitatively for the age dependence of cancer incidence, or for the fact that the incidence of cancer in people with hereditary mutations in tumour suppressor genes is much lower than expected, or for the observation that while in some types of cancer, like colon and pancreas, certain highly oncogenic mutations, such as that of TP53, are prevalent, there is no significant increase in the incidence of these cancers in people who carry the mutations by heredity. It is argued here that although mutations in such 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 large numbers of cells. Conceivably, the mutations directly underlying neoplastic transformation may be the result of a local collapse in the system of intercellular processes on which the stability of the normal genotype and phenotype depends, and thereby trigger a cascade of mutations, among them the highly oncogenic ones. This local collapse may be due to mutations of many different genes in many cells as well as to other factors affecting the integrity of tissue.
Steen
H B
HB
Department of Biophysics, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, Oslo, N-0310 Norway E-mail: h. b.steen@labmed.uio.no.
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics; D009857:Oncogenes / Q000235:genetics*