Journal Article

Identification and chromosome mapping of loci predisposing to colorectal cancer that control Wnt/β-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

in Carcinogenesis

Volume 28, issue 11, pages 2367-2374
Published in print November 2007 | ISSN: 0143-3334
Published online May 2007 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgm119
Identification and chromosome mapping of loci predisposing to colorectal cancer that control Wnt/β-catenin pathway and progression of early lesions in the rat

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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/SegHsd × Wistar-Furth)F2 (AWF2) rats to map susceptibility genes influencing the evolution of early colorectal lesions to adenocarcinoma following 1,2-dimethylhydrazine administration. Phenotypic analysis revealed higher incidence/multiplicity and lower size of adenomas in ACI/SegHsd (ACI) and (ACI/SegHsd × Wistar-Furth)F1 (AWF1) than Wistar-Furth (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 three 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 rCcr49 and a locus on chromosome 5 was identified as a susceptibility locus, rCcs1. Significant interactions between rCcr3 and rCcr6, rCcr6 and rCcr8 and rCcr5 and rCcr9, and four 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/β-catenin pathway was shown by defective β-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.

Journal Article.  6618 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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