Evidence for complex multigenic inheritance of radiation AML susceptibility in mice revealed using a surrogate phenotypic assay.
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.
Darakhshan
F
F
Radiation Effects Department, Health Protection Agency, Radiation Protection Division, Chilton, Didcot, Oxfordshire, OX11 0RQ, UK.
Badie
C
C
Moody
J
J
Coster
M
M
Finnon
R
R
Finnon
P
P
Edwards
A A
AA
Szluinska
M
M
Skidmore
C J
CJ
Yoshida
K
K
Ullrich
R
R
Cox
R
R
Bouffler
S D
SD
D000208:Acute Disease; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002874:Chromosome Mapping; D004706:Endodeoxyribonucleases; D004720:Endonucleases; D023381:Endpoint Determination; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D040582:Inheritance Patterns; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000662:veterinary; D007953:Leukemia, Radiation-Induced / Q000235:genetics* / Q000662:veterinary; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018895:Microsatellite Repeats; D005810:Multigene Family; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D010641:Phenotype; D015854:Up-Regulation; D018797:Cell Cycle Proteins
D002352:Carrier Proteins; D004706:Endodeoxyribonucleases; D004720:Endonucleases; D005819:Genetic Markers; D009687:Nuclear Proteins; C501070:RBBP8 protein, mouse; D018797:Cell Cycle Proteins