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Carcinogenesis Advance Access published online on April 15, 2008
Carcinogenesis, doi:10.1093/carcin/bgn094
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Lack of DNA mismatch repair protein MSH6 in the rat results in hereditary non-polyposis colorectal cancer-like tumorigenesis

Ruben van Boxtel1, Pim Toonen1, Henk van Roekel1, Mark Verheul1, Bart M. G. Smits1,3, Jeroen Korving1, Alain de Bruin2 and Edwin Cuppen1,*

1 Hubrecht Institute for Developmental Biology and Stem Cell Research, Cancer Genomics Center, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
2 Utrecht University, Faculty of Veterinary Medicine, Department of Pathobiology, Yalelaan 1, 3584 CL Utrecht, The Netherlands

* Corresponding author: Hubrecht Institute for Developmental Biology and Stem Cell Research, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands. E-mail: e.cuppen{at}niob.knaw.nl, Tel: +31 30 2121969, Fax: +31 30 2516554

To understand genetic instability in relation to tumorigenesis experimental animal models have proven very useful. The DNA mismatch repair (MMR) machinery safeguards genomic integrity by repairing mismatches, insertion/deletion loops and responding to genotoxic agents. Here, we describe the functional characterization of a novel rat mutant model in which the mismatch repair gene Msh6 has been genetically inactivated by N-ethyl-N-nitrosourea (ENU)-driven target-selected mutagenesis. This model shows a robust mutator phenotype that is reflected by microsatellite instability and an increased germ line point mutation frequency. Consequently these rats develop a spectrum of tumors with a high similarity to atypical hereditary non-polyposis colorectal cancer in humans. The MSH6 knockout rat complements existing models for studying genetic instable tumorigenesis as it provides experimental opportunities that are not available or suboptimal in current models.

3 Current address: Department of Oncology, McArdle Laboratory for Cancer Research, 1400 University Avenue, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA

Received January 3, 2008; revised March 17, 2008; accepted April 5, 2008.


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