Abstract
The risk of cancer after exposure to ionizing radiation is currently defined only as a function of the received dose. Genetic factors that modify individual susceptibility to radiation-induced cancer are excluded from the risk assessment. We report the mapping of QTLs that confer increased susceptibility to radiation-induced osteosarcoma in the mouse. The strongest candidate locus, on chromosome 14, contains a functional polymorphism weakening the efficiency of the Rb1 promoter. The Rb1 allele associated with increased susceptibility is preferentially retained during allelic loss at the Rb1 gene in radiation-induced tumors. In combination with allelic losses of CDKN2a/P16, an upstream regulator of Rb1, 100% of all analyzed tumors exhibit a defect affecting this pathway. Alpha-irradiation of knockout mice with a bone-specific expression reduction of Rb1 or P16 confirmes that these genes can alter the susceptibility for osteosarcoma, either by increasing the tumor-risk or by shortening their latency. These results suggest that common germ-line polymorphisms causing impaired expression of known tumor-suppressor genes can modify individual susceptibility to radiation-induced cancer.
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Acknowledgement
This work was supported by a grants from the European Commission (EURATOM) FIGH-CT99- 00001 and from the German ministry BMBF (KVSF 03NUK007).
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Rosemann, M., González-Vasconcellos, I., Domke, T., Nathrath, M., Atkinson, M.J. (2012). Reduced Rb1 Expression Causes Impaired Genome Stability in Bone-Cells and Predispose for Radiation-Induced Osteosarcoma. In: Mothersill, C., Korogodina, V., Seymour, C. (eds) Radiobiology and Environmental Security. NATO Science for Peace and Security Series C: Environmental Security. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-1939-2_29
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DOI: https://doi.org/10.1007/978-94-007-1939-2_29
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