Mouse models of DNA mismatch repair in cancer research

Abstract

Germline mutations in DNA mismatch repair (MMR) genes are the cause of hereditary non-polyposis colorectal cancer/Lynch syndrome (HNPCC/LS) one of the most common cancer predisposition syndromes, and defects in MMR are also prevalent in sporadic colorectal cancers. In the past, the generation and analysis of mouse lines with knockout mutations in all of the known MMR genes has provided insight into how loss of individual MMR genes affects genome stability and contributes to cancer susceptibility. These studies also revealed essential functions for some of the MMR genes in B cell maturation and fertility. In this review, we will provide a brief overview of the cancer predisposition phenotypes of recently developed mouse models with targeted mutations in MutS and MutL homologs (Msh and Mlh, respectively) and their utility as preclinical models. The focus will be on mouse lines with conditional MMR mutations that have allowed more accurate modeling of human cancer syndromes in mice and that together with new technologies in gene targeting, hold great promise for the analysis of MMR-deficient intestinal tumors and other cancers which will drive the development of preventive and therapeutic treatment strategies.

Targeting immune checkpoints potentiates immunoediting and changes the dynamics of tumor evolution

“…Thus, it is an imperative to characterize the applied mouse models and the evolutionary forces driving the tumor in order to dissect the contribution of individual components on shaping the cancer genome. Over and above, since MMR deficiency predicts response to checkpoint blockade in 12 different solid tumor types 45 , further studies using genetically engineered mouse models 46 could help to identify molecular determinants that make not only CRC tumors sensitive to immune checkpoint blockade, but possibly also other tumor types.…”

The Clinical Impact of the Genomic Landscape of Mismatch Repair–Deficient Cancers

“…In contrast, Msh3 and Mlh3 that are involved in other MMR pathways have a milder phenotype. Msh4 and Msh5 have an essential role in meiotic recombination but not in cancer (106).…”

Eukaryotic Mismatch Repair in Relation to DNA Replication

“…MMR proteins also modulate cellular responses to environmental stress, prevent recombination between diverged sequences, modulate development of the immune system, influence the stability of trinucleotide repeat sequences associated with degenerative diseases, and participate in meiosis. All of these subjects continue to garner widespread interest, as evidenced by the large number of review articles on the functions of MMR proteins published this year alone (4, 12, 20, 24, 33, 41, 43, 44, 53, 59, 72, 74–77, 86, 108, 109, 113a, 127, 150). The broad range of topics covered in these reviews allows us to focus this review on relationships between MMR and nuclear DNA replication.…”