Five quantitative trait loci control radiation-induced adenoma multiplicity in Mom1R Apc Min/+ mice.
Ionising radiation is a carcinogen capable of inducing tumours, including colorectal cancer, in both humans and animals. By backcrossing a recombinant line of Apc(Min/+) mice to the inbred BALB/c mouse strain, which is unusually sensitive to radiation-induced tumour development, we obtained panels of 2Gy-irradiated and sham-irradiated N2 Apc(Min/+) mice for genotyping with a genome-wide panel of microsatellites at approximately 15 cM density and phenotyping by counting adenomas in the small intestine. Interval and composite interval mapping along with permutation testing identified five significant susceptibility quantitative trait loci (QTLs) responsible for radiation induced tumour multiplicity in the small intestine. These were defined as Mom (Modifier of Min) radiation-induced polyposis (Mrip1-5) on chromosome 2 (log of odds, LOD 2.8, p = 0.0003), two regions within chromosome 5 (LOD 5.2, p<0.00001, 6.2, p<0.00001) and two regions within chromosome 16 respectively (LOD 4.1, p = 4x10(-5), 4.8, p<0.00001). Suggestive QTLs were found for sham-irradiated mice on chromosomes 3, 6 and 13 (LOD 1.7, 1.5 and 2.0 respectively; p<0.005). Genes containing BALB/c specific non-synonymous polymorphisms were identified within Mrip regions and prediction programming used to locate potentially functional polymorphisms. Our study locates the QTL regions responsible for increased radiation-induced intestinal tumorigenesis in Apc(Min/+) mice and identifies candidate genes with predicted functional polymorphisms that are involved in spindle checkpoint and chromosomal stability (Bub1b, Casc5, and Bub1), DNA repair (Recc1 and Prkdc) or inflammation (Duox2, Itgb2l and Cxcl5). Our study demonstrates use of in silico analysis in candidate gene identification as a way of reducing large-scale backcross breeding programmes.
Elahi
Eiram
E
Colorectal Cancer Genetics, Institute for Cell and Molecular Sciences, Barts and The London, Queen Mary's School of Medicine and Dentistry, London, United Kingdom.
Suraweera
Nirosha
N
Volikos
Emmanouil
E
Haines
Jackie
J
Brown
Natalie
N
Davidson
Gerovie
G
Churchman
Mike
M
Ilyas
Mohammed
M
Tomlinson
Ian
I
Silver
Andrew
A
D000236:Adenoma / Q000235:genetics* / Q000473:pathology*; D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000596:Amino Acids / Q000235:genetics; D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics; D019295:Computational Biology; D005819:Genetic Markers; D016678:Genome / Q000235:genetics; D054501:Group II Phospholipases A2 / Q000378:metabolism*; D007421:Intestine, Small / Q000473:pathology; D008126:Lod Score; D051379:Mice; D009154:Mutation / Q000235:genetics; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D011110:Polymorphism, Genetic; D011506:Proteins / Q000378:metabolism*; D040641:Quantitative Trait Loci / Q000235:genetics*; D012641:Selection, Genetic
D025601:Adenomatous Polyposis Coli Protein; D000596:Amino Acids; D005819:Genetic Markers; D011506:Proteins; D054501:Group II Phospholipases A2; C516288:Pla2g2a protein, mouse