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Carcinogenesis Advance Access originally published online on April 15, 2008
Carcinogenesis 2008 29(6):1290-1297; 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 W. Toonen1, Henk S. 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 Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands
3 Present address: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, 1400 University Avenue, Madison, WI 53706, USA

* To whom correspondence should be addressed. Tel: +31 30 2121969;, Fax: +31 30 2516554; Email: e.cuppen{at}niob.knaw.nl

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 or deletion loops and responding to genotoxic agents. Here, we describe the functional characterization of a novel rat mutant model in which the MMR gene Msh6 has been genetically inactivated by N-ethyl-N-nitrosourea-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.

Abbreviations: ENU, N-ethyl-N-nitrosourea; HNPCC, hereditary non-polyposis colorectal cancer; MMR, mismatch repair; MSI, microsatellite instability; PCR, polymerase chain reaction

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


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