caa a22 4500 445812729 CHVBK 20180317145216.0 cr unu---uuuuu 170323e20110301xx s 000 0 eng 10.1007/s00411-010-0339-4 doi (NATIONALLICENCE)springer-10.1007/s00411-010-0339-4 Differential effects of genes of the Rb1 signalling pathway on osteosarcoma incidence and latency in alpha-particle irradiated mice [Elektronische Daten] [Iria Gonzalez-Vasconcellos, Tanja Domke, Virginija Kuosaite, Irene Esposito, Bahar Sanli-Bonazzi, Michaela Nathrath, Michael Atkinson, Michael Rosemann] Osteosarcoma is the most frequent secondary malignancy following radiotherapy of patients with bilateral retinoblastoma. This suggests that the Rb1 tumour suppressor gene might confer genetic susceptibility towards radiation-induced osteosarcoma. To define the contribution of the Rb1 pathway in the multistep process of radiation carcinogenesis, we evaluated somatic allelic changes affecting the Rb1 gene itself as well as its upstream regulator p16 in murine osteosarcoma induced by 227Th incorporation. To distinguish between the contribution of germline predisposition and the effect of a 2-hit allelic loss, two mouse models harbouring heterozygote germline Rb1 and p16 defects were tested for the incidence and latency of osteosarcoma following irradiation. We could show that all tumours arising in BALB/c×CBA/CA hybrid mice (wild-type for Rb1 and for p16) carried a somatic allelic loss of either the Rb1 gene (76.5%) or the p16 gene (59%). In none of the tumours, we found concordant retention of heterozygosity at both loci. Heterozygote knock-out mice for Rb1 exhibit a significant increase in the incidence of osteosarcoma following 227Th incorporation (22/24 in Rb1+/− vs. 2/18 in Rb1+/+, p=4×10−5), without affecting tumour latency. In contrast, heterozygote knock-out mice for p16 had no significant change in tumour incidence, but a pronounced reduction of latency (LT50%=355days in p16+/− vs. 445days in p16+/+, p=8×10−3). These data suggest that Rb1 germline defects influence early steps of radiation osteosarcomagenesis, whereas alterations in p16 mainly affect later stages of tumour promotion and growth. Springer-Verlag, 2010 Gonzalez-Vasconcellos Iria Institute of Radiation Biology, Helmholtz Zentrum München, Neuherberg, Germany aut Domke Tanja Institute of Radiation Biology, Helmholtz Zentrum München, Neuherberg, Germany aut Kuosaite Virginija Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany aut Esposito Irene Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany aut Sanli-Bonazzi Bahar Institute of Radiation Biology, Helmholtz Zentrum München, Neuherberg, Germany aut Nathrath Michaela Clinical Cooperation Group Osteosarcoma, Helmholtz Zentrum München and TU München, Neuherberg, Germany aut Atkinson Michael Institute of Radiation Biology, Helmholtz Zentrum München, Neuherberg, Germany aut Rosemann Michael Institute of Radiation Biology, Helmholtz Zentrum München, Neuherberg, Germany aut Radiation and Environmental Biophysics Springer-Verlag 50/1(2011-03-01), 135-141 0301-634X 50:1<135 2011 50 411 https://doi.org/10.1007/s00411-010-0339-4 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00411-010-0339-4 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Gonzalez-Vasconcellos Iria Institute of Radiation Biology, Helmholtz Zentrum München, Neuherberg, Germany aut NATIONALLICENCE 700 1- Domke Tanja Institute of Radiation Biology, Helmholtz Zentrum München, Neuherberg, Germany aut NATIONALLICENCE 700 1- Kuosaite Virginija Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany aut NATIONALLICENCE 700 1- Esposito Irene Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany aut NATIONALLICENCE 700 1- Sanli-Bonazzi Bahar Institute of Radiation Biology, Helmholtz Zentrum München, Neuherberg, Germany aut NATIONALLICENCE 700 1- Nathrath Michaela Clinical Cooperation Group Osteosarcoma, Helmholtz Zentrum München and TU München, Neuherberg, Germany aut NATIONALLICENCE 700 1- Atkinson Michael Institute of Radiation Biology, Helmholtz Zentrum München, Neuherberg, Germany aut NATIONALLICENCE 700 1- Rosemann Michael Institute of Radiation Biology, Helmholtz Zentrum München, Neuherberg, Germany aut NATIONALLICENCE 773 0- Radiation and Environmental Biophysics Springer-Verlag 50/1(2011-03-01), 135-141 0301-634X 50:1<135 2011 50 411 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer