A two-locus system controls susceptibility to colitis-associated colon cancer in mice

Oncotarget. 2010 Oct;1(6):436-446. doi: 10.18632/oncotarget.177.

Abstract

We have previously shown that the differential susceptibility of A/J (susceptible) and C57BL/6J (B6, resistant) mouse strains to azoxymethane (AOM)-induced colorectal cancer (CRC) is controlled by the chromosome 3 locus, Ccs3. We report that A/J and B6 mice also show differential susceptibility to colitis-associated colorectal cancer (CA-CRC) induced by combined administration of AOM and dextran sulfate. This differential susceptibility is not controlled by Ccs3, but is under distinct genetic control. Linkage analyses in (A/J x B6)F2 mice detected a major CA-CRC susceptibility locus on chromosome 9 (Ccs4) which controls tumor multiplicity and tumor surface area. Susceptibility alleles at Ccs4 are inherited in a recessive fashion, with A/J alleles being associated with susceptibility. We also detected a second locus on chromosome 14 that acts in an additive fashion with Ccs4. Strikingly, F2 mice homozygous for A/J alleles at both loci (Ccs4 and chromosome 14) are as susceptible to CA-CRC as the A/J controls while mice homozygous for B6 alleles are as resistant as the B6 controls, thus supporting the role of two interacting loci in this CA-CRC model. This indicates that susceptibility to chemically-induced CRC and susceptibility to CA-CRC are under distinct genetic control in mice, and probably involve distinct cellular pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azoxymethane / toxicity
  • Carcinogens / toxicity
  • Chromosome Mapping
  • Chromosomes, Mammalian / genetics*
  • Colitis / chemically induced
  • Colitis / genetics*
  • Colitis / pathology
  • Colorectal Neoplasms / chemically induced
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Crosses, Genetic
  • Disease Models, Animal
  • Female
  • Genetic Linkage
  • Genetic Loci*
  • Genetic Predisposition to Disease*
  • Male
  • Mice
  • Mice, Inbred A
  • Mice, Inbred C57BL
  • Quantitative Trait Loci / genetics*

Substances

  • Carcinogens
  • Azoxymethane