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Background  Syndromic forms of osteosarcoma (OS) account for less than 10% of all recorded cases of this malignancy. An individual OS predisposition is also possible by the inheritance of low penetrance alleles of tumor susceptibility genes, usually without evidence of a syndromic condition. Genetic variants involved in such a non-syndromic form of tumor predisposition are difficult to identify, given the low incidence of osteosarcoma cases and the genetic heterogeneity of patients. We recently mapped a major OS susceptibility QTL to mouse chromosome 14 by comparing alpha-radiation induced osteosarcoma in mouse strains which differ in their tumor susceptibility.    Methods  Tumor-specific allelic losses in murine osteosacoma were mapped along chromosome 14 using microsatellite markers and SNP allelotyping. Candidate gene search in the mapped interval was refined using PosMed data mining and mRNA expression analysis in normal osteoblasts. A strain-specific promoter variant in  Rb 1 was tested for its influence on mRNA expression using reporter assay.    Results  A common  Rb1  allele derived from the BALB/cHeNhg strain was identified as the major determinant of radiation-induced OS risk at this locus. Increased OS-risk is linked with a hexanucleotide deletion in the promoter region which is predicted to change WT1 and SP1 transcription factor-binding sites. Both  in-vitro  reporter and  in-vivo  expression assays confirmed an approx. 1.5 fold reduced gene expression by this promoter variant. Concordantly, the 50% reduction in  Rb1  expression in mice bearing a conditional hemizygous  Rb1  deletion causes a significant rise of OS incidence following alpha-irradiation.    Conclusion  This is the first experimental demonstration of a functional and genetic link between reduced  Rb1  expression from a common promoter variant and increased tumor risk after radiation exposure. We propose that a reduced  Rb1  expression by common variants in regulatory regions can modify the risk for a malignant transformation of bone cells after radiation exposure.

A Rb1 promoter variant with reduced activity contributes to osteosarcoma susceptibility in irradiated mice