A combination of epidemiological, experimental animal and cellular molecular data is used in the estimation of tumor risk after low doses of low-LET radiation. Uncertainties are recognized in the interpretation of all these data sets, and recent findings concerning genomic instability in irradiated cells challenge the conventional view that induced DNA damage is expressed during the immediate post irradiation cell cycle. These data on genomic instability are based largely upon studies of cell cultures- the mechanisms involved and implications for tumor formation in living organisms remain unclear. Nevertheless, if induced genomic instability were to have unusual dose-response characteristics and could be shown to dominate low dose tumorigenesis, then there might be new implications for the estimation of radiation risk at low doses.

1. Establish the mechanistic basis of radiation-associated genomic instability
   
   
2. Assess whether such induced instability might play a major role in tumorigenic response and risk from low doses of low-LET radiation.

There are few studies on living organisms on which to base judgement on the role of genetic background and genomic instability on cancer risk. Recent work with a mouse model using radiation-exposed breast cells provide the first indications that certain forms of genetically determined induced genomic instability may contribute to tumor development. In this model, susceptibility to induced genomic instability is expressed as an autosomal recessive trait in mammary epithelial cells and is manifest largely as excess chromatid damage many cell divisions after the radiation exposure. Recently, published studies associate this form of instability with DNA repair deficiency, polymorphic variation in the gene encoding DNA PKcs and mammary gland cancer susceptibility.

Characterize the distribution and chromosomal specificity of radiation-induced instability, the subsequent appearance of critical clonal chromosomal aberrations in cells expressing instability, and the potential involvement of clonal selection in the pathogenesis of mammary cancer. Subsequent studies will identify the specific genomic regions involved in mammary cancer and test whether mammary specific genes are associated with such regions. The underlying hypothesis being tested is that tumor-associated genomic instability is preferentially expressed in certain recombinogenic genomic domains and that these domains may be cell lineage-specific.