Individual genetic susceptibility and radiation carcinogenesis
Radiation carcinogenesis group
Leader: Dr. Michael Rosemann
The deterministic and stochastic responses to ionizing radiation vary between individuals. This variability confounds the prediction of adverse health effects to an individual that are made by extrapolating from population-based risk. Apart from well described high penetrance mutations, inherited allele-variations with a rather quantitative phenotypic effect have the potential to modify the extent of the individual susceptibility to ionizing radiation. In its most dramatic form this leads to acute radiation hypersensitivity or increased risk of cancer. Our challenge is to understand the processes that shape individual genetic susceptibility, and to use this knowledge to develop accurate methods to predict individual risk.
Based on genetic mapping strategies (Somatic allelic imbalance and germ line QTL mapping) to identify genes influencing the development of radiation-induced cancers in various laboratory mouse strains, we could identify five epistatic mouse loci, one encoding a functional polymorphism of the Rb1 promoter, modify sensitivity to α-induced osteosarcoma (colaboration with Dr. J.Favor, HMGU IHG). To understand the underlying molecular and genetic mechanisms, we established osteoblast cultures from bone-specific conditional Rb1-knockout mice and investigate changes in their chromosomal stability.
Another focus of our studies are thyroid-neoplasia, that can be induced by pre- and postnatal treatment of mice with radio-iodine 131I. It was found, that a yet uncharacterized gene from JF1 wild-mice can suppress the formation of these tumors (colaboration with HMGU Pathology).
We are involved in a colaborative effort with the Research-Center for Radiation Medicine (Dr. med. S.Klymenko) to identify molecular alterations in Acute-Myeloid Leukaemia cases that occurred in clean-up workers at the Tschernobyl NPP accident. Here we could show that overproportional many cases exhibit losses of chromosome 5 and 7, which are typical for patients with a poor disease prognosis. In addition, a relatively large number of cases carry multiple tandem-duplications in the Flt3 proto-oncogene, whereas AML1-ETO translocations were unusually rare.