Genetic susceptibility for radiation effects

Radiation carcinogenesis group

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, 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.

 

 

Image: ISB

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 Pathology, Helmholtz Zentrum München).

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.

Publications

Rosemann M, Gonzalez-Vasconcellos I, Domke T, Kuosaite V, Schneider R, Kremer M, Favor J, Nathrath M, Atkinson MJ. A Rb1 promoter variant with reduced activity contributes to osteosarcoma susceptibility in irradiated mice. Mol Cancer. 2014 Aug 4;13:182.

Gonzalez-Vasconcellos I, Anastasov N, Sanli-Bonazzi B, Klymenko O, Atkinson MJ, Rosemann M. Rb1 haploinsufficiency promotes telomere attrition and radiation-induced genomic instability. Cancer Res. 2013 Jul 15;73(14):4247-55.

Alessio N, Bohn W, Rauchberger V, Rizzolio F, Cipollaro M, Rosemann M, Irmler M, Beckers J, Giordano A, Galderisi U. Silencing of RB1 but not of RB2/P130 induces cellular senescence and impairs the differentiation potential of human mesenchymal stem cells. Cell Mol Life Sci. 2013 May;70(9):1637-51.

Rümenapp C, Smida J, Gonzalez-Vasconcellos I, Baumhoer D, Malfoy B, Hadj-Hamou NS, Sanli-Bonazzi B, Nathrath M, Atkinson MJ, Rosemann M. Secondary radiation-induced bone tumours demonstrate a high degree of genomic instability predictive of a poor prognosis. Curr Genomics. 2012 Sep;13(6):433-7.

Finnon R, Brown N, Moody J, Badie C, Olme CH, Huiskamp R, Meijne E, Sutmuller M, Rosemann M, Bouffler SD. Flt3-ITD mutations in a mouse model of radiation-induced acute myeloid leukaemia. Leukemia. 2012 Jun;26(6):1445-6.

Heidenreich WF, Rosemann M. Genetic background and 227Thorium as risk factors in biologically based models for induction of bone cancer in mice. Radiat Environ Biophys. 2012 May;51(2):179-85.

Dalke C, Hölzlwimmer G, Calzada-Wack J, Quintanilla-Martinez L, Atkinson MJ, Rosemann M. Differences in the susceptibility to iodine¹³¹-induced thyroid tumours amongst inbred mouse strains. J Radiat Res. 2012;53(3):343-52.

Klymenko SV, Smida J, Atkinson MJ, Bebeshko VG, Nathrath M, Rosemann M. Allelic imbalances in radiation-associated acute myeloid leukemia. Genes (Basel). 2011 May 31;2(2):384-93.

Gonzalez-Vasconcellos I, Domke T, Kuosaite V, Esposito I, Sanli-Bonazzi B, Nathrath M, Atkinson MJ, Rosemann M. Differential effects of genes of the Rb1 signalling pathway on osteosarcoma incidence and latency in alpha-particle irradiated mice. Radiat Environ Biophys. 2011 Mar;50(1):135-41.

Rosemann M, Kuosaite V, Kremer M, Favor J, Quintanilla-Martinez L, Atkinson MJ. Multilocus inheritance determines predisposition to alpha-radiation induced bone tumourigenesis in mice. Int J Cancer. 2006 May 1;118(9):2132-8.

Klymenko S, Trott K, Atkinson M, Bink K, Bebeshko V, Bazyka D, Dmytrenko I, Abramenko I, Bilous N, Misurin A, Zitzelsberger H, Rosemann M. Aml1 gene rearrangements and mutations in radiation-associated acute myeloid leukemia and myelodysplastic syndromes. J Radiat Res. 2005 Jun;46(2):249-55.

Heidenreich WF, Müller WA, Paretzke HG, Rosemann M. Bone cancer risk in mice exposed to 224Ra: protraction effects from promotion. Radiat Environ Biophys. 2005 May;44(1):61-7. Epub 2005 Apr 27.

Klymenko SV, Bink K, Trott KR, Bebeshko VG, Bazyka DA, Dmytrenko IV, Abramenko IV, Bilous NI, Zitzelsberger H, Misurin AV, Atkinson MJ, Rosemann M. MLL gene alterations in radiation-associated acute myeloid leukemia. Exp Oncol. 2005 Mar;27(1):71-5.

Abiola O, Angel JM, Avner P, Bachmanov AA, Belknap JK, Bennett B, Blankenhorn EP, Blizard DA, Bolivar V, Brockmann GA, .... Rosemann M, ....Zou F; Complex Trait Consortium. The nature and identification of quantitative trait loci: a community's view. Nat Rev Genet. 2003 Nov;4(11):911-6. Review.

Group Photos