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(American Journal of Pathology. 2007;170:377-387.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060853

Aneuploidy Arises at Early Stages of Apc-Driven Intestinal Tumorigenesis and Pinpoints Conserved Chromosomal Loci of Allelic Imbalance between Mouse and Human

Paola Alberici*, Emma de Pater*, Joana Cardoso*, Mieke Bevelander*, Lia Molenaar*, Jos Jonkers{dagger} and Riccardo Fodde*

From the Department of Pathology,* Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam; and the Division of Molecular Biology,{dagger} The Netherlands Cancer Institute, Amsterdam, The Netherlands

Although chromosomal instability characterizes the majority of human colorectal cancers, the contribution of genes such as adenomatous polyposis coli (APC), KRAS, and p53 to this form of genetic instability is still under debate. Here, we have assessed chromosomal imbalances in tumors from mouse models of intestinal cancer, namely Apc+/1638N, Apc+/1638N/KRASV12G, and Apc+/1638N/Tp53–/–, by array comparative genomic hybridization. All intestinal adenomas from Apc+/1638N mice displayed chromosomal alterations, thus confirming the presence of a chromosomal instability defect at early stages of the adenoma-carcinoma sequence. Moreover, loss of the Tp53 tumor suppressor gene, but not KRAS oncogenic activation, results in an increase of gains and losses of whole chromosomes in the Apc-mutant genetic background. Comparative analysis of the overall genomic alterations found in mouse intestinal tumors allowed us to identify a subset of loci syntenic with human chromosomal regions (eg, 1p34-p36, 12q24, 9q34, and 22q) frequently gained or lost in familial adenomas and sporadic colorectal cancers. The latter indicate that, during intestinal tumor development, the genetic mechanisms and the underlying functional defects are conserved across species. Hence, our array comparative genomic hybridization analysis of Apc-mutant intestinal tumors allows the definition of minimal aneuploidy regions conserved between mouse and human and likely to encompass rate-limiting genes for intestinal tumor initiation and progression.




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K. Aoki and M. M. Taketo
Adenomatous polyposis coli (APC): a multi-functional tumor suppressor gene
J. Cell Sci., October 1, 2007; 120(19): 3327 - 3335.
[Abstract] [Full Text] [PDF]


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