Genetic Analysis of Colon Cancer Susceptibility in Mice

Jacoby, Russell F.; Hohman, Colleen; Marshall, David J.; Frick, Terrence J.; Schlack, Steven; Broda, Michelle; Smutko, John S.; Elliott, Rosemary W.

doi:10.1006/geno.1994.1399

Cited by 59 publications

(34 citation statements)

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“…B6.129 non-DKO mice with at least one WT allele of Gpx1 or Gpx2 rarely had inflammation and none had tumors. Genetic background has a profound effect on both inflammation (16) and tumor susceptibility (25), with B6 being resistant to inflammation but sensitive to chemicalinduced colon carcinogenesis. We back-crossed our original colony of B6.129 Gpx1/2-DKO to B6 mice and investigated whether B6 Gpx1/2-DKO mice are also more resistant to inflammation and inflammation-associated cancer than B6.129 Gpx1/2-DKO mice.…”

Section: Resultsmentioning

confidence: 99%

Mutation Accumulation in the Intestine and Colon of Mice Deficient in Two Intracellular Glutathione Peroxidases

Lee¹,

Esworthy

Chu

et al. 2006

Cancer Research

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Mice deficient in two glutathione peroxidases (GPX), Gpx1 and Gpx2, [Gpx1/2-double knockout (DKO) mice] are prone to ileocolitis on a mixed C57BL/6 and 129S1/SvJ (B6.129) genetic background. We reported previously that f25% of B6.129 Gpx1/2-DKO mice develop ileocolonic tumors by 6 to 9 months of age, when their non-DKO littermates [having at least one wild-type (WT) Gpx1 or Gpx2 allele] rarely have inflammation and none have tumors. Because genetic background affects tumor susceptibility, we have generated a B6 Gpx1/2-DKO colony and discovered that these mice have fewer inflammatory cells, milder ileocolitis, and low mortality, and only 2.5% of B6 mice developed tumors. The mutant frequency of a cII reporter gene was about 2-to 3-fold higher in 28-day-old Gpx1/2-DKO and 4-fold higher in 8-month-old Gpx1/2-DKO ileal mucosa than in controls in both genetic backgrounds. In contrast, mutant frequencies in the unaffected B6 liver were not significantly different between WT and Gpx1/ 2-DKO mice. The mutant frequency of 8-month-old B6.129 Gpx1/2-DKO ileum was 38.94 F 15.5 À5 , which was not significantly higher than the age-matched B6 ileum, 25.54 F 10.33 À5. The mutation spectra analysis has shown that B6 Gpx1/2-DKO ileum had a 3-fold increase in small nucleotide deletions at mononucleotide repeats over control B6, which are a signature mutation associated with oxidative stress. Unexpectedly, B6 Gpx1/2-DKO mice had fewer C to T transitions at CpG dinucleotides than the WT B6 (18.0% versus 40.1%; P < 0.001). Our results suggest that inflammation drives gene mutations, which leads to neoplastic transformation of intestinal epithelium in the B6.129 Gpx1/2-DKO mice but rarely in the B6 Gpx1/2-DKO mice.

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Section: Resultsmentioning

confidence: 99%

Mutation Accumulation in the Intestine and Colon of Mice Deficient in Two Intracellular Glutathione Peroxidases

Lee¹,

Esworthy

Chu

et al. 2006

Cancer Research

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“…The most significant association in the Scc3 was located at 176.7 Mb on chromosome 1 (rs32121685, P ¼ 3.47 Â 10 -4 ; Table 2). The refined Scc3 locus includes 10 annotated Chromosome -log(P) -log(P) 11 genes, of which Fmn2 and Grem2 are major candidates. The Scc2 locus on chromosome 2 (rs28039498, P ¼ 2.09 Â 10 -4 ) covers 7 genes, of which Fap, Ifih1, and Gca are strong candidates.…”

Section: Fine Mapping Of Previous Linkage Regionsmentioning

confidence: 99%

“…A number of linkage mapping studies with cross-breeding experiments were carried out for chemically induced colon tumors in mice (11)(12)(13)(14)(15)(16). As a result, 16 quantitative trait loci (QTL) responsible for chemically induced colon tumors have been mapped on the mouse genome, implying a very complex picture of inherited susceptibility of colon tumorigenesis exists.…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Association and Fine Mapping of Genetic Loci Predisposing to Colon Carcinogenesis in Mice

Liu

Lü

Liu

et al. 2012

Molecular Cancer Research

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To identify the genetic determinants of colon tumorigenesis, 268 male mice from 33 inbred strains derived from different genealogies were treated with azoxymethane (AOM; 10 mg/kg) once a week for six weeks to induce colon tumors. Tumors were localized exclusively within the distal colon in each of the strains examined. Inbred mouse strains exhibit a large variability in genetic susceptibility to AOM-induced colon tumorigenesis. The mean colon tumor multiplicity ranged from 0 to 38.6 (mean ¼ 6.5 AE 8.6) and tumor volume ranged from 0 to 706.5 mm 3 (mean ¼ 87.4 AE 181.9) at 24 weeks after the first dose of AOM. AOM-induced colon tumor phenotypes are highly heritable in inbred mice, and 68.8% and 71.3% of total phenotypic variation in colon tumor multiplicity and tumor volume, respectively, are attributable to strain-dependent genetic background. Using 97,854 single-nucleotide polymorphisms, we carried out a genome-wide association study (GWAS) of AOM-induced colon tumorigenesis and identified a novel susceptibility locus on chromosome 15 (rs32359607, P ¼ 6.31 Â 10 -6 ). Subsequent fine mapping confirmed five (Scc3, Scc2, Scc12, Scc8, and Ccs1) of 16 linkage regions previously found to be associated with colon tumor susceptibility. These five loci were refined to less than 1 Mb genomic regions of interest. Major candidates in these loci are Sema5a, Fmn2, Grem2, Fap, Gsg1l, Xpo6, Rabep2, Eif3c, Unc5d, and Gpr65. In particular, the refined Scc3 locus shows high concordance with the human GWAS locus that underlies hereditary mixed polyposis syndrome. These findings increase our understanding of the complex genetics of colon tumorigenesis, and provide important insights into the pathways of colorectal cancer development and might ultimately lead to more effective individually targeted cancer prevention strategies. Mol Cancer Res; 10(1); 66-74. Ó2011 AACR.

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“…21 Segregation analysis in informative crosses derived from mouse strains of different susceptibility has suggested that susceptibility to CRC in mice has a complex genetic component, as is the case in humans. Several quantitative trait loci (QTLs) regulating CRC susceptibility in mice have been mapped in different crosses, including Ccs1, 22 Scc1, 23 and Ccs2. 24 Of interest, Ptprj gene was shown to be responsible for the Scc1 effect, and …”

Section: Resultsmentioning

confidence: 99%

Genetic control of susceptibility to carcinogen-induced colorectal cancer in mice: TheCcs3andCcs5loci regulate different aspects of tumorigenesis

Meunier

Kwan²,

Turbide³

et al. 2011

Cell Cycle

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Genetic Analysis of Colon Cancer Susceptibility in Mice

Cited by 59 publications

References 0 publications

Mutation Accumulation in the Intestine and Colon of Mice Deficient in Two Intracellular Glutathione Peroxidases

Mutation Accumulation in the Intestine and Colon of Mice Deficient in Two Intracellular Glutathione Peroxidases

Genome-Wide Association and Fine Mapping of Genetic Loci Predisposing to Colon Carcinogenesis in Mice

Genetic control of susceptibility to carcinogen-induced colorectal cancer in mice: TheCcs3andCcs5loci regulate different aspects of tumorigenesis

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