RGD Reference Report - Identification and chromosome mapping of loci predisposing to colorectal cancer that control Wnt/{beta}-catenin pathway and progression of early lesions in the rat. - Rat Genome Database

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Identification and chromosome mapping of loci predisposing to colorectal cancer that control Wnt/{beta}-catenin pathway and progression of early lesions in the rat.

Authors: De Miglio, MR  Virdis, P  Calvisi, DF  Mele, D  Muroni, MR  Frau, M  Pinna, F  Tomasi, ML  Simile, MM  Pascale, RM  Feo, F 
Citation: De Miglio MR, etal., Carcinogenesis. 2007 May 17;.
RGD ID: 1625309
Pubmed: (View Article at PubMed) PMID:17510081
DOI: Full-text: DOI:10.1093/carcin/bgm119

Sporadic colorectal cancer (CRC) is a major health concern worldwide. Epidemiologic evidence suggests a polygenic predisposition to CRC, but the genes responsible remain unknown. Here, we performed genome-wide scanning of male (ACI x Wistar-Furth)F2 (AWF2) rats to map susceptibility genes influencing the evolution of early colorectal lesions to adenocarcinoma following dimethylhydrazine administration. Phenotypic analysis revealed higher incidence/multiplicity and lower size of adenomas in ACI and AWF1 than WF rats, and higher incidence/multiplicity of poorly differentiated adenocarcinomas in WF than ACI rats, with intermediate values in AWF1 rats. Linkage analysis of 138 AWF2 rats identified 3 loci on chromosomes 4, 15, and 18, in significant linkage with lesion multiplicity that were identified as rat Colon cancer resistance (rCcr) 1, rCcr2, and rCcr3, respectively. Seven other loci on chromosomes 5, 6, 15, 17, 18, and 20, were in suggestive linkage with adenoma/adenocarcinoma multiplicity/surface area. Six of them were identified as rCcr4-9,and a locus on chromosome 5, was identified as a susceptibility locus, rCcs1. Significant interactions between rCcr3 and rCcr6, cRcr6 and rCcr8, and rCcr5 and rCcr9, and 4 novel epistatic loci controlling multiplicity/size of colorectal lesions were discovered. Apc, located at rCcr3, did not show functional promoter polymorphisms. However, influence of susceptibility/resistance genes on Wnt/beta-catenin pathway was shown by defective beta-catenin inactivation in WF but not in ACI and AWF1 rat adenocarcinomas. These data indicate that inheritance of predisposition to CRC depends on interplays of several genetic factors, and suggest a possible mechanism of polygenic control of CRC progression.



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Phenotype Annotations    

Mammalian Phenotype

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Objects Annotated

QTLs
Colcr1  (Colorectal carcinoma resistance QTL 1)
Colcr2  (Colorectal carcinoma resistance QTL 2)
Colcr3  (Colorectal carcinoma resistance QTL 3)
Colcr4  (Colorectal carcinoma resistance QTL4)
Colcr5  (Colorectal carcinoma resistance QTL 5)
Colcr6  (Colorectal carcinoma resistance QTL 6)
Colcr7  (Colorectal carcinoma resistance QTL 7)
Colcr8  (Colorectal carcinoma resistance QTL 8)
Colcr9  (Colorectal carcinoma resistance QTL 9)
Colcs1  (Colorectal carcinoma susceptibility QTL 1)

Strains
ACI/SegHsd  (NA)
WF/CrCrli  (NA)


Additional Information