ers 2001). This same Prkdc polymorphism has also been implicated in radiation-induced lymphomagenesis, as a modifier of induced intestinal neoplasia in Apcmin mice (Degg and others 2003), and as a candidate gene for the Rapop1 apoptosis-controlling locus (Mori and others 2001). Other tissue-specific loci that control apoptosis have also been genomically mapped (e.g., Weil and others 2001).

With respect to breast cancer susceptibility in mice, it is already clear that loci other than Prkdc can be involved (Moser and others 2001). From recent studies, it seems likely that one such gene is ATM, which in the heterozygous form can enhance the frequency of both genomic instability and ductal dysplasia of the breast of irradiated mice (Weil and others 2001).


Although much remains to be learned about genetic susceptibility to the tumorigenic effects of radiation, it is possible to frame some interim conclusions of the role it may play in determining radiation cancer risk at the individual and population levels.

The principal point to emphasize is that cancer is a multifactorial set of diseases, and as such, there is expected to be a complex interplay between multiple germline genes and a plethora of other host- and environment-related factors. The data available, although far from complete, tend to support this basic expectation. The key issues and arguments are given here in brief summary.

For rare major gene deficiencies in humans and mice, there can be strong effects on radiation cancer risk, and for individual carriers, it seems likely that the greatest implications may be for the risk of second cancers after RT (see ICRP 1998). Although the data are sparse, such high-dose radiation exposure in childhood may carry the greatest risk. However, due to differences in genetic background, a uniformity of tumorigenic response in RT patients with major gene deficiencies should not be expected.

The fact that strongly expressing cancer-prone disorders are so rare argues against a significant impact and distorting effect on estimates of cancer risk in irradiated populations; population genetic modeling fully supports this view (see ICRP 1998). By contrast, at the level of whole populations it is feasible that certain inherited combinations of common low-penetrance genes can result in the presence of subpopulations having significantly different susceptibilities to spontaneous and radiation-associated cancer. In due course, the accumulation of sufficient molecular epidemiologic data may allow for some meaningful theoretical modeling of the distribution of radiation cancer risk and the possible implications for radiological protection. Irrespective of such modeling, risk estimates based on epidemiologic evaluation of whole populations will encompass this projected genetic heterogeneity of response. Therefore, the key issue is not whether the estimate of overall cancer risk is genetically confounded, but rather the extent to which genetic distortion of the distribution of this risk might lead to underprotection of an appreciable fraction of the population. In this respect, some initial guidance for thought is already available from the data discussed in this chapter.

These data suggest large numbers of loci of low penetrance with relatively small individual effects and a significant degree of locus-specific interaction and tissue specificity that may apply to their activity. Projecting this scenario to a range of radiogenic tumors in a genetically heterogeneous human population would tend to lead to a situation in which the balance between a certain set of tumor susceptibility (S) and resistance (R) loci in a given subgroup might serve to emphasize risk in a given set of organs. Equally, however, the balance of additional S and R locus combinations might provide a degree of resistance to the induction and development of cancer in other organs. Thus, with this first genetic scenario, major distortions of the distribution of overall cancer risk after radiation might not apply simply because different genetic susceptibilities would tend to “average out” across organs. By contrast, a second hypothetical scenario involves a small subset of common polymorphic loci that exert organ-wide effects on tumor susceptibility or resistance, which might be particularly strong in the specific instance of radiation exposure (e.g., functional polymorphisms for genes involved in initial tissue-wide cellular response to radiation damage). In this instance, genetically determined distortion of the distribution of overall cancer risk might be expected. At present, the data available are insufficient to distinguish the likely contributions from these two genetic scenarios.

Finally, the large study of cancer concordance in 90,000 Nordic twin pairs should be noted. Lichtenstein and colleagues (2000) and Hoover (2000) make some important points about the difficulties that exist in separating the genetic and environmental components of cancer. In essence, Hoover notes that this Nordic study, like others, is consistent with the presence of low-penetrance cancer-predisposing genes in the general population. However, the confidence intervals for the heritable component of cancers at common sites were wide—all ranged from around 5 to 50%. It was also pointed out that for cancer at common sites, the rate of concordance in monozygotic twins was generally less than 15%. Thus, the absolute risk of concordance of site-specific cancer in identical genotypes sharing some common environmental factors is rather low. In addition to this, a study based on the Swedish Family Cancer Database (Czene and others 2002) has provided further information on the genetic component of organ-specific cancer. With the exception of the thyroid, the environment appears to have the principal causal role for cancer at all sites.

One important message that emerges from current data on cancer genes of low penetrance and the overall genetic component of cancer is that predictive genotyping of individuals for the purposes of radiological protection may not

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