. "3 Radiation-Induced Cancer: Mechanisms, Quantitative Experimental Studies and the Role of Genetic Factors." Health Risks from Exposure to Low Levels of Ionizing Radiation: BEIR VII Phase 2. Washington, DC: The National Academies Press, 2006.
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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2
future, the growing capacity of molecular screening techniques to detect cancer-susceptible genotypes in the general population will, in principle, allow the radiation risk of such genotypes to be assessed in a number of suitable human cohorts. A summary of such molecular epidemiologic approaches to spontaneous cancer risk is given later in this chapter.
Population Modeling of Radiation Cancer Risk: Impact of Strongly Expressing Genetic Disorders
In conjunction with the work of an ICRP (1998) Task Group, Chakraborty and colleagues (1997, 1998a) have constructed and illustrated the use of a population-based computational model that serves to describe the impact of cancer-susceptible genotypes on radiation cancer risk in the population. For reasons of data sufficiency, breast cancer risk in typical Western populations was considered and illustrated. This approach, which is based on established Mendelian principles, employed best estimates of the prevalence of known, high-penetrance breast cancer-predisposing genes (BRCA1 and BRCA2), the relative risk of spontaneous breast cancer in such genotypes, and a range of factors that describe in a hypothetical fashion the increase in radiation risk imposed by the given gene mutations; the risk of radiogenic breast cancer in normal individuals was based on data from Japanese atomic bomb survivors.
Other issues that were considered included increased gene frequency in certain genetically isolated populations (Ashkenazi Jews) and the influence of reduced penetrance on population risk. The following points summarize the outcome of these modeling exercises.
Using best estimates of breast cancer gene frequencies, the genetic impact on excess breast cancer in an irradiated Western population would be small even if these mutations were to impose a radiation risk that was as much as a hundredfold greater than that of normal genotypes.
Using estimates of the higher gene frequencies in Ashkenazi Jewish populations, the genetic impact on radiation-associated breast cancer can become significant but only if the genetically imposed radiation risk is very high.
The genetic impact of such mutations will be diluted in proportion to decreasing penetrance.
This model and its predictions have been used by the ICRP (1998) and NRPB (1999) to provide interim judgments on the implications of genetic susceptibility to cancer for radiological protection.
Since the overall prevalence of highly penetrant cancer-predisposing mutations in typical human populations is judged to be 1% or less (ICRP 1998) and since available data tend to argue against extreme increases in genetically imposed radiation cancer risk, there is reason to believe that the presence of these rare, highly penetrant mutations will not appreciably distort current estimates of radiation cancer risk in the population. Stated simply, only a very small fraction of excess cancers in an irradiated human population are expected to arise in individuals carrying familial cancer genes.
The ICRP (1998) and NRPB (1999) stressed, however, that this conclusion took no account of the presence of potentially more common cancer genes of low penetrance that do not express familial cancer. The ICRP and NRPB reports also commented on the problems inherent in identifying and making judgments about radiation cancer risk in genetic subgroups carrying such weakly expressing genes and considered the issue of genetically imposed risk to individuals. These matters are discussed in subsequent sections.
Genes of Low Penetrance
As noted earlier in this chapter, knowledge of heritable factors in tumorigenesis stems largely from studies on strongly predisposing autosomal dominant familial traits and autosomal recessive disorders having unambiguous phenotypes. The problem of estimating the heritable impact on cancer risk from weakly expressing genes of low penetrance and other genetic modifiers of the cancer process has been with us for some time. However, not unexpectedly, an understanding of this issue is proving difficult to obtain. To a large measure this is due to the likelihood that, individually, polymorphic variant genes probably contribute small additional cancer risks to each carrier in a largely tissue-specific manner. These will tend to escape detection by conventional medical genetic and epidemiologic studies. A combination of such genes and their interaction with environmental risk factors may, however, provide a substantial genetic component to both spontaneous and radiation-associated risk. The magnitude of this risk in a given human population would then be determined by gene frequencies together with the pattern or strength of gene-gene and gene-environment interactions.
These issues of population cancer risk have been discussed widely in the context of epidemiologic and molecular genetic findings (Hoover 2000; Houlston and Tomlinson 2000; Lichtenstein and others 2000; Peto and Mack 2000; Shields and Harris 2000; Dong and Hemminki 2001; Nathanson and Weber 2001; Ponder 2001). Here it is sufficient to illustrate some of the progress being made in respect of the weakly expressing genetic component of human and animal tumorigenesis. Where possible, emphasis is placed on data having some connection with cancer risk after ionizing radiation.
Human Breast Cancer
BRCA1 and BRCA2 genes have been identified as the principal genetic determinants of the 2–5% of breast cancer that expresses in multiple-case families; other, more weakly expressing genes involved in familial breast cancer remain