Abstract
Background: The loss or low expression of DNA mismatch repair (MMR) genes can result in genomic instability and tumorigenesis. One such gene, MSH2, is mutated or rearranged in Lynch syndrome (LS), which is characterized by a high risk of tumor development, including colorectal cancer. However, many variants identified in this gene are often defined as variants of uncertain significance (VUS). In this study, we selected a variant in the 3′ untranslated region (UTR) of MSH2 (c*226A > G), identified in three affected members of a LS family and already reported in the literature as a VUS. Methods: The effect of this variant on the activity of the MMR complex was examined using a set of functional assays to evaluate MSH2 expression. Results: We found MSH2 was overexpressed compared to healthy controls, as determined by RTqPCR and Western blot analyses of total RNA and proteins, respectively, extracted from peripheral blood samples. These results were confirmed by luciferase reporter gene assays. Conclusions: We therefore speculated that, in addition to canonical inactivation via a gene mutation, MMR activity may also be modulated by changes in MMR gene expression.
Highlights
The loss or low expression of MSH2 in particular, and that of other DNA mismatch repair (MMR) genes, results in genomic instability and a predisposition to cancer [1,2]
It has been described that the overexpression of MLH1 and/or MSH2 induces apoptosis and/or a mutator phenotype with genetic instability [3,4,5]
Microsatellite instability (MSI) is an important molecular marker for the characterization of a mutator phenotype linked to MMR genes [6]
Summary
The loss or low expression of MSH2 in particular, and that of other DNA mismatch repair (MMR) genes, results in genomic instability and a predisposition to cancer [1,2]. Microsatellite instability (MSI) is an important molecular marker for the characterization of a mutator phenotype linked to MMR genes [6]. The loss or low expression of DNA mismatch repair (MMR) genes can result in genomic instability and tumorigenesis. One such gene, MSH2, is mutated or rearranged in Lynch syndrome (LS), which is characterized by a high risk of tumor development, including colorectal cancer.
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