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Carcinogenesis Advance Access published online on May 17, 2007
Carcinogenesis, doi:10.1093/carcin/bgm119
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Maria R. De Miglio, Patrizia Virdis, Diego F. Calvisi, Daniela Mele, Maria R. Muroni, Maddalena Frau, Federico Pinna, Maria L. Tomasi, Maria M. Simile, Rosa M. Pascale and Francesco Feo

Department of Biomedical Sciences, Division of Experimental Pathology and Oncology, University of Sassari. Sassari, Italy

Request for reprints: Francesco Feo, Department of Biomedical Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy. Phone: 0039-079-228307; Fax: 0039-079-228485; E-mail: feo{at}uniss.it

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/ß-catenin pathway was shown by defective ß-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.

Key Words: Genetic susceptibility • colorectal carcinogenesis • modifier gene • ß-catenin • Apc

Received February 1, 2007; revised May 8, 2007; accepted May 12, 2007.


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