title: DNA mismatch repair deficiency accelerates lung neoplasm development in K-ras(LA1/+) mice: a brief report.
abstract: Inherited as well as acquired deficiencies in specific DNA mismatch repair (MMR) components are associated with the development of a wide range of benign and malignant neoplasms. Loss of key members such as MSH2 and MLH1 severely cripples the ability of the cell to recognize and correct such lesions as base:base mismatches and replicative DNA polymerase errors such as slippages at repetitive sequences. Genomic instability resulting from MMR deficiency not only predisposes cells to malignant transformation but may also promote tumor progression. To test the latter, we interbred Msh2(-/-) mice with the K-ras(LA1/+) transgenic line that spontaneously develops a range of premalignant and malignant lung lesions. Compared to K-ras(LA1/+) mice, K-ras(LA1/+); Msh2(-/-) mice developed lung adenomas and adenocarcinomas at an increased frequency and also demonstrated evidence of accelerated adenocarcinoma growth. Since MMR defects have been identified in some human lung cancers, the mutant mice may not only be of preclinical utility but they will also be useful in identifying gene alterations able to act in concert with Kras mutants to promote tumor progression.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Calgary, 3280 Hospital Drive NW, Calgary, Alberta, Canada, T2N 4Z6.
authors.forename: Charlene M
authors.initials: CM
authors.lastname: Downey
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Calgary, 3280 Hospital Drive NW, Calgary, Alberta, Canada, T2N 4Z6.
authors.forename: Frank R
authors.initials: FR
authors.lastname: Jirik
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D053843:DNA Mismatch Repair / Q000235:genetics*; D018450:Disease Progression; D011905:Genes, ras / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics*; D008822:Mice, Transgenic; D051718:MutS Homolog 2 Protein / Q000172:deficiency*; D009154:Mutation / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000172:deficiency*
chemical_list: C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Adenocarcinoma; DNA mismatch repair; K-ras; Msh2; NSCLC