The mapping of genes which affect individual cancer risk is an important but complex challenge. A surrogate assay of susceptibility to radiation-induced acute myeloid leukaemia (AML) in the mouse based on chromosomal radiosensitivity has been developed and validated. This assay was applied to the mapping of radiation-induced AML risk modifier loci by association with microsatellite markers. A region on chromosome (chr) 18 with strong association is identified and confirmed by backcross analysis. Additional loci on chrs 8 and 13 show significant association. A key candidate gene Rbbp8 on chr18 is identified. Rbbp8 is shown to be upregulated in response to X-irradiation in the AML sensitive CBA strain but not AML resistant C57BL/6 strain. This study demonstrates the strength of utilizing surrogate endpoints of cancer susceptibility in the mapping of mouse loci and identifies additional loci that may affect radiation cancer risk.
Bibliographical noteFunding Information:
The authors thank Graham Bailey for assisting with statistical analyses. The authors are grateful to Prof. John Todd for providing NOD mice and MRC, Harwell for use of radiation facilities. This work was funded by EU contracts MAGELLANS (FIGH-CT-1999-00035) and RISC-RAD (FI6R-CT-2003-508842). F.D. was supported by an extra-mural research grant to the University of Reading from the National Radiological Protection Board.