Impact of cancer predisposition and radiosensitivity on the population risk of radiation-induced cancers.

Abstract

This paper provides a brief overview of the current evidence for cancer predisposition and for an increased sensitivity of individuals carrying such predisposing mutations to cancers induced by ionizing radiations. We also discuss the use of a Mendelian one-locus, two-allele autosomal dominant model for predicting the impact of cancer predisposition and increased radiosensitivity on the risk of radiation-induced cancers in the population and in relatives of affected individuals using breast cancer due to BRCA1 mutations as an example. The main conclusions are the following: (1) The relative risk ratio of the risks of radiation-induced cancer in a heterogeneous population which has subgroups of normal and cancer-predisposed individuals to the risks in a homogeneous population (i.e., one which does not have these subgroups) increases with increasing dose; however, the dose dependence of the RR decreases at higher doses because of the fact that at high doses, the radiation risk to a homogeneous population will already be high. (2) The attributable risk (the proportion of cancers attributable to increased cancer susceptibility and increased radiosensitivity) follows a similar pattern. (3) When the proportion of cancers due to the susceptible genotypes is small (< 10%), as is likely to be the case for breast cancers in non-Ashkenazi Jewish women, the increases in risk ratios and attributable risks are small, and become marked only when there are very large increases in cancer susceptibility (> 1000-fold) and radiosensitivity (> 100-fold) in the susceptible group. (4) When the proportion of cancers due to the susceptible genotypes is appreciable (> or = 10%), as may be the case for breast cancers in Ashkenazi Jewish women, there may be significant increases in the risk ratios and attributable risk for comparatively moderate increases in cancer susceptibility (> 10-fold) and radiosensitivity (> 100-fold) in the susceptible subpopulation. (5) The ratio of the risk of radiation-induced cancer in relatives to that in unrelated individuals in the population increases with the biological relatedness of the relative, being higher for close than for distant relatives; however, even when the mutant BRCA1 gene frequency and the proportion of breast cancers due to these mutations are high, as in Ashkenazi Jewish women, for values of predisposition strength and radiosensitivity differential < 10, the increase in breast cancer risks is only marginal, even for first-degree relatives.