Darakhshan, F. et al. Evidence for complex multigenic inheritance of radiation AML susceptibility in mice revealed using a surrogate phenotypic assay. Carcinogenesis 27, 311-318

Radiation Effects Department, Health Protection Agency, Radiation Protection Division, Chilton, Didcot, Oxfordshire, OX11 0RQ, UK.
Carcinogenesis (Impact Factor: 5.33). 03/2006; 27(2):311-8. DOI: 10.1093/carcin/bgi207
Source: PubMed


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.

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    • "The human ortholog RBBP8 is a suspected tumor suppressor found on our own chromosome 18. Deletions of Rbbp8 have been identified in many cancers including AML [111]. "
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    • "Further evidence for complex multigenic inheritance of rML susceptibility in mice has been found on several other chromosomes (e.g. chr8, chr13, and chr18) (Darakhshan et al.2006). "
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    • "Similarly, evidence is abundant for strain differences in mice (Okumoto et al. 1990, Kamisaku et al. 2000, Vogelsang et al. 2009). The CBA strain is among those that are susceptible to radiation-induced acute myeloid leukemia (AML), whereas C57BL/6 mice are resistant (Darakhshan et al. 2006, Giotopoulos et al. 2006). Over the course of a typical 20–24 month lifespan, spontaneous incidence of AML in CBA mice is rare, but increases to 20–25% after a single dose of 3 Gy X-rays (Major 1979). "
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