Cancer predisposition, radiosensitivity and the risk of radiation-induced cancers. I. Background.

This paper presents an overview of current knowledge on genetic predisposition to cancer and on enhanced sensitivity of cancer-predisposed genotypes to cancers induced by ionizing radiation. It is intended to provide a background and set the stage for the next papers in this series in which we will assess how such heterogeneity (with respect to predisposition to cancer and presence of radiosensitivity genotypes) in a population may affect estimates of the risk of radiation-induced cancers. The main findings and/or conclusions of the present paper are the following: (1) "Cancer-predisposing genes" (i.e. those at which germinal mutations predispose to cancer) are present in the human genome; these genes are responsible not only for the rare familial cancer syndromes but also for a proportion of the common cancers. At least 21 such genes have now been cloned (including 9 tumor suppressor genes, 11 DNA repair genes and 1 proto-oncogene); further, at least 8 putative tumor suppressor genes and a gene involved in ataxia telangiectasia have been localized to specific chromosomes. (2) These genes play crucial roles in the control of cellular proliferation, programmed cell death (apoptosis) and/or one or another DNA repair pathway. Consequently, mutations in these genes are likely to "liberate" the cells from the normal constraints imposed by them, resulting in unconstrained growth characteristic of cancer. (3) At present, the evidence for increased sensitivity of cancer-predisposed genotypes to radiation-induced cancers is limited. However, current knowledge of the known functions of the cancer-predisposing genes and of the consequences of mutations in these provide (a) sufficient grounds for assuming that the genotypes of those predisposed to cancer may be at an increased risk for radiation-induced cancers and (b) the rationale for attempts to estimate quantitatively the impact of genotype-dependent differences in cancer predisposition and radiosensitivity on cancer risks in an irradiated population.