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

Carcinogenesis
Ruben van BoxtelEdwin Cuppen

Abstract

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.

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Citations

Jun 10, 2010·The Pharmacogenomics Journal·R van BoxtelE Cuppen
May 7, 2011·Current Opinion in Nephrology and Hypertension·Guanyi HuangQi-Long Ying
Aug 23, 2011·The American Journal of Pathology·Ruben van BoxtelEdwin Cuppen
Jul 17, 2013·Psychoneuroendocrinology·Elodie M GiraultAndries Kalsbeek
Jun 27, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Zarry TavakkolAndy J Chien
Aug 24, 2012·Nature·Alexey Kondrashov
Nov 26, 2009·American Journal of Physiology. Endocrinology and Metabolism·Joram D MulEdwin Cuppen
Jul 1, 2011·The Journal of Biological Chemistry·Joram D MulEdwin Cuppen
Oct 5, 2010·Genome Biology·Ruben van Boxtel, Edwin Cuppen
May 8, 2021·Frontiers in Genetics·Vanessa ChenouardIgnacio Anegon

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