title: Genetic control of susceptibility to carcinogen-induced colorectal cancer in mice: the Ccs3 and Ccs5 loci regulate different aspects of tumorigenesis.
abstract: Colorectal cancer (CRC) is a multistep disease that involves a two-way interaction between a complex genetic pre-disposition component, and a set of poorly understood extrinsic environmental factors. In mice, CRC can be induced by treatment with azoxymethane (AOM). Using a set of AcB/BcA recombinant congenic strains derived from CRC-susceptible A/J and CRC-resistant C57Bl/6J (B6) progenitors, we previously detected the Ccs3 locus (colon cancer susceptibility locus 3) as a major regulator of CRC susceptibility. Phenotyping of additional AcB/BcA strains for susceptibility to AOM-induced CRC has refined the Ccs3 interval to a 6.7 Mb segment on chromosome 3. In addition, the presence of intermediate susceptibility phenotypes in individual AcB/BcA strains suggested additional gene effects regulating CRC susceptibility in A/J and B6 strains. Those were investigated by linkage analysis and whole genome scanning in a set of 208 informative (B6 x A/J)F2 progeny, using tumor multiplicity as a quantitative measure of susceptibility. This analysis validated the important role of Ccs3 in regulating this trait, and additionally detected contribution from a second locus on the distal portion of chromosome 9 (LOD = 3.76), that was given the temporary designation of Ccs5. Ccs5 modulates tumor multiplicity in F2 animals bearing at least one A/J-derived susceptibility allele at Ccs3, with A/J-derived Ccs5 susceptibility alleles being inherited in a recessive manner. There is a strong additive effect of Ccs3 and Ccs5 on tumor multiplicity in F2 mice: mice doubly homozygotes for A/J or B6 alleles at Ccs3 and Ccs5 show tumor numbers similar to those of parental A/J and B6, respectively. Interestingly, the Ccs5 region overlaps several quantitative trait loci previously reported to regulate intestinal homeostasis and susceptibility to intestinal colitis in mice and humans. Our findings identify a novel two-locus system regulating CRC susceptibility in mice, of which the relevance to human CRC can now be tested experimentally.
authors.affiliation: McGill University, Montreal, Quebec, Canada.
authors.forename: Charles
authors.initials: C
authors.lastname: Meunier
authors.forename: Tony
authors.initials: T
authors.lastname: Kwan
authors.forename: Claire
authors.initials: C
authors.lastname: Turbide
authors.forename: Nicole
authors.initials: N
authors.lastname: Beauchemin
authors.forename: Philippe
authors.initials: P
authors.lastname: Gros
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics; D002875:Chromosomes; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000209:etiology / Q000235:genetics*; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics*; D010641:Phenotype
chemical_list: D002273:Carcinogens; C491962:Ccs protein, mouse; D018832:Molecular Chaperones