Multilocus inheritance determines predisposition to α-radiation induced bone tumourigenesis in mice
Article first published online: 5 DEC 2005
Copyright © 2005 Wiley-Liss, Inc.
International Journal of Cancer
Volume 118, Issue 9, pages 2132–2138, 1 May 2006
How to Cite
Rosemann, M., Kuosaite, V., Kremer, M., Favor, J., Quintanilla-Martinez, L. and Atkinson, M. J. (2006), Multilocus inheritance determines predisposition to α-radiation induced bone tumourigenesis in mice. Int. J. Cancer, 118: 2132–2138. doi: 10.1002/ijc.21612
- Issue published online: 21 FEB 2006
- Article first published online: 5 DEC 2005
- Manuscript Accepted: 12 SEP 2005
- Manuscript Received: 15 JUN 2005
- EU Radiation Protection Program. Grant Number: FIGH-CT99-00001
- genetic susceptibility
In a recent study, we presented evidence for genetic predisposition governing radiation osteosarcomagenesis in mice. Following the incorporation of the bone-seeking α emitter 227Th, ˜25% of the variance in osteosarcoma incidence was determined by inherited genetic factors. We have now mapped 5 susceptibility loci in crosses between the more susceptible BALB/c and the more resistant CBA/Ca strains. The major QTL on chromosome 14 overlaps with a locus that was already found in our previous study, using different strains of mice. Here, we investigate the effect by which the major susceptibility locus and 4 minor modifier loci interact to influence osteosarcoma predisposition. Following incorporation of the bone-seeking isotope, 100% of mice that harbour high-risk genotypes at all 5 susceptibility loci develop osteosarcoma with an average of 472 days latency times. In 10 mice inheriting exclusively low-risk genotypes only 1 osteosarcoma was found, arising after 733 days latency time. Inheritance of distinct combinations of BALB/c and CBA/Ca alleles at the susceptibility loci confer more extreme phenotypes in terms of susceptibility or resistance than observed in either of the two parental inbred strains. From the present study, we demonstrate that additive effects of multiple alleles, each making only a minor phenotypic contribution, can combine and significantly alter tumour risk. This mechanism can be of particular importance in genetically heterogeneous populations such as man. © 2005 Wiley-Liss, Inc.