and are consistent with knowledge of the somatic mechanisms of tumorigenesis reviewed earlier in this chapter. In particular, evidence has been obtained that major deficiencies in DNA damage response and tumor-suppressor-type genes can serve to elevate radiation cancer risk. Limited epidemiologic data from follow-up of second cancers in gene carriers receiving radiotherapy were supportive of the above conclusions, but quantitative judgments about the degree of increased cancer risk remain uncertain. However, since major germline deficiencies in the genes of interest are known to be rare, it is possible to conclude from published analyses that they are most unlikely to create a significant distortion of population-based estimates of cancer risk. The major practical issue associated with these strongly expressing cancer genes is judged to be the risk of radiotherapy-related cancer.

A major theme developing in the whole field of cancer genetics is the interaction and potential impact of more weakly expressing variant cancer genes that may be relatively common in human populations. Knowledge of such gene-gene and gene-environment interactions, although at an early stage, is developing rapidly. The animal genetic data reviewed in this chapter provide proof-of-principle evidence of how such variant genes with functional polymorphisms can influence cancer risk, including limited data on radiation tumorigenesis. Attention has also been given to recent molecular epidemiology data on associations between functional polymorphisms and cancer risk, particularly with respect to DNA damage response genes. Some issues of study design have been discussed, and although much work has been reported on cancer risk in heterozygous carriers of the ATM gene, clear judgments about radiation risks remain elusive.

Given that functional gene polymorphisms associated with cancer risk may be relatively common, the potential for significant distortion of population-based risk was explored, with emphasis on the organ specificity of the genes of interest. A preliminary conclusion is that common polymorphisms of DNA damage response genes associated with organ-wide radiation cancer risk would be the most likely source of major interindividual differences in radiation response.

Although good progress is being made, there are important gaps in understanding the extent of genetic influences on radiation cancer risk. Accordingly, further work is needed in humans and mice on gene mutations and functional polymorphisms that influence radiation response and cancer risk. Human molecular genetic studies should, where possible, be coupled with epidemiologic investigations.

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