have provided evidence on the potential impact of GSTM1 allelic status on tobacco-related lung cancer risk.
The broad but incomplete picture that emerges from these studies is of some associations between gene polymorphisms and risk for a range of human tumor types, as well as the clear need for larger and more definitive studies.
It has already been noted that DNA repair genes play a crucial role in cellular responses to radiation and that major germline deficiencies in these genes can lead to heritable predisposition to cancer. Accordingly, considerable effort is being expended in the search for common functional polymorphisms that might act as low-penetrance cancer susceptibility genes.
A series of studies have identified common and less common polymorphisms in around ten DNA repair genes, some of which appear to have cellular consequences (Price and others 1997; Shen and others 1998; Mohrenweiser and Jones 1998; Duell and others 2000). The associations between these polymorphisms and radiosensitivity and/or tumor risk remain unclear, although there are some positive indications (Duell and others 2001; Hu and others 2001). Much of this work has centered on genes involved in base- or nucleotide-excision repair (Miller and others 2001). Studies on genes controlling DNA DSB repair are less well developed. However, there are indications that a relatively common (in ~6% of the population) functional polymorphism in the XRCC2 gene of the homologous recombinational repair pathway for DNA DSBs associates with a modestly increased risk of breast cancer (Kuschel and others 2002; Rafii and others 2002). A significant association between breast cancer risk and certain polymorphisms of NHEJ DNA repair has also been reported (Fu and others 2003). A recent review of DNA repair gene polymorphisms and cancer risk recommends large, well-designed studies that include consideration of relevant exposures (Goode and others 2002).
The recognized difficulties of resolving the modifying effects of low-penetrance genes on human cancer risk have prompted experimental genetic studies with rodent models in which genetic-environmental interactions can be more closely controlled.
This approach has been applied principally in mice for the study of naturally arising polymorphic variation that influences spontaneous cancer risk and the risk after exposure to chemical carcinogens and, in a few instances, ionizing radiation (Balmain and Nagase 1998). These studies have the capacity to provide proof-of-principle evidence of the impact of such common loci, together with their possible interactions and tissue specificity, as well as the classes of genes and mechanisms involved. Thus, although specific functional gene polymorphisms identified in mice may not predict those of humans precisely, the overall pattern of cancer risk modification should provide broad guidance on the potential for such effects in humans.
Much of the research on the role of germline polymorphic loci in mouse tumorigenesis has centered on spontaneous and chemically induced neoplasms. These studies include tumors of the skin (e.g., Nagase and others 2001; Peissel and others 2001), lung (e.g., Lee and others 2001; Tripodis and others 2001), and intestinal tract (e.g., van Wezel and others 1996; Angel and others 2000). The most important messages to emerge from these studies are that multiple common loci can exert complex patterns of control over tumor susceptibility and resistance (synergistic and antagonistic interaction), that the loci tend to be relatively tissue specific in their activity, and that genetic determinants of spontaneous and induced tumorigenesis are often shared. A particularly revealing conclusion from the study of Tripodis and colleagues (2001) is that as many as 60 loci may interact to determine the risk of a single tumor type; specific pairwise interaction of a proportion of these loci was also demonstrated.
A second approach used in mouse genetic studies is to seek evidence of natural polymorphic loci that modify the tumorigenic expression of a major cancer-predisposing germline mutation. In this way, evidence has been obtained for substantial genetic modification of tumorigenesis in Trp53- (Backlund and others 2001) and Apc-deficient mice (van der Houven van Oordt and others 1999; Moser and others 2001). In the case of Apc, one of these modifier genes (Pla2g2a) has been identified provisionally (Cormier and others 2000). In general, these effects of genetic modifiers are again consistent with the potential interaction of multiple tissue-specific loci, and some of the data relate to tumors induced by ionizing radiation.
Some studies in this area have the specific objective of mapping and characterizing the polymorphic loci that influence tumorigenic radiosensitivity and tumor characteristics. Multiple loci have been shown to influence susceptibility to radiation-induced lymphoma and leukemia (Balmain and Nagase 1998; Szymanska and others 1999; Saito and others 2001; Santos and others 2001). One study of Boulton and colleagues (2001) provided evidence that the AML loci determining leukemia or lymphoma susceptibility were distinct from those that influenced genomic instability in bone marrow cells. However, no candidate genes were identified. Genetic loci influencing the susceptibility of mice to α-particle (227Th)-induced osteosarcoma have also been mapped (Rosemann and others 2002), but again, no candidate genes were specifically identified.
By contrast, another set of investigations has associated a strain-specific functional polymorphism of the gene Prkdc encoding DNA PKcs with induced genomic instability, DNA DSB repair deficiency, and susceptibility to radiation-induced breast cancer (Okayasu and others 2000; Yu and oth-