For the purpose of the constructing biologically-based computation models of low dose radiation tumorigenesis it is important to gain a better understanding of the radiation-associated somatic events that contribute to neoplasia and the influence of germ line genetic variation on tumour risk. This proposal from four EU partners seeks to exploit recent developments in mouse tumorigenesis and mouse-human genome research to address these issues in models of induced leukaemia, lymphoma and skin tumours. Emphasis is placed upon early radiation associated genomic events, multistep tumour development, germ line gene variation and radiation tumorigenesis.
The outcome of the project at the mid-term point is:
i) The provision of molecular genetic and cytogenetic data on critical gene loss and chromosome breakage events in myeloid leukaemia and lymphoma. Also on the genetic factors that influence myeloid leukaemia susceptibility via a mechanism involving chromatin-remodelling;
ii) The successful development of a new mouse model of radiation-induced basal cell skin cancer and medulloblastoma of the central nervous system; also data on radiation-associated gene loss in tumours;
iii) The provision of further data on the complex interaction of genetic factors in determining skin cancer susceptibility in the mouse including the identification of 3 candidate genes, also, data on a locus influencing both skin and lung tumorigenesis and genetic associations between tumour susceptibility and inflammatory response;
iv) Completion of the construction of a 1.7 MB mouse database detailing the relative genomic positions of genes involved in DNA damage response/repair and loci associated with cancer susceptibility; also, the provision of evidence linking functional polymorphism of the Prkdc repair-related gene with in vivo radiosensitivity and breast and intestinal cancer risk in the mouse. These data maybe integrated into a single result concerning the mechanisms/genetics of radiation tumorigenesis and the possible implications for radiological protection;
v) The principal implications of the project work for radiological protection are:
1) That the somatic mechanisms of radiation tumorigenesis are consistent with those predicted by in vitro cellular data and add weight to the view that there is a simple proportionate relationship between dose and cancer risk;
2) That variant germ line genes interact in a complex manner to determine radiation cancer risk; these interactions are usually but not always tissue-specific and cross-sensitivity to different carcinogenic agents is generally expected.
Funding SchemeCSC - Cost-sharing contracts