Open AccessDNA mismatch repair deficiency accelerates lung neoplasm development in K‐ras LA1/+ mice: a brief report
Author(s) -
Downey Charlene M.,
Jirik Frank R.
Publication year - 2015
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.420
Subject(s) - kras , cancer research , msh2 , dna mismatch repair , genetically modified mouse , adenocarcinoma , mlh1 , biology , malignant transformation , mutation , genome instability , lung , dna repair , cancer , gene , transgene , medicine , dna , dna damage , genetics
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 MSH 2 and MLH 1 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.