Abstract
Lynch syndrome confers an increased risk to various types of cancer, in particular early onset colorectal and endometrial cancer. Mutations in mismatch repair (MMR) genes underlie Lynch syndrome, with the majority of mutations found in MLH1 and MSH2. Mutations in MSH6 have also been found but these do not always cause a clear cancer predisposition phenotype and MSH6-defective tumors often do not show the standard characteristics of MMR deficiency, such as microsatellite instability. In particular, the consequences of MSH6 missense mutations are challenging to predict, which further complicates genetic counseling. We have previously developed a method for functional characterization of MSH2 missense mutations of unknown significance. This method is based on endogenous gene modification in mouse embryonic stem cells using oligonucleotide-directed gene targeting, followed by a series of functional assays addressing the MMR functions. Here we have adapted this method for the characterization of MSH6 missense mutations. We recreated three MSH6 variants found in suspected Lynch syndrome families, MSH6-P1087R, MSH6-R1095H and MSH6-L1354Q, and found all three to behave like wild type MSH6. Thus, despite suspicion for pathogenicity from clinical observations, our approach indicates these variants are not disease causing. This has important implications for counseling of mutation carriers.
Highlights
Lynch Syndrome (LS), called hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant disorder that is characterized by early onset cancer of the colorectum and endometrium
We have selected three MSH6 variants of uncertain significance (VUS) that have been found in suspected Lynch syndrome families: hMSH6-P1087R, hMSH6R1095H and hMSH6-L1354Q
The hMSH6-R1095H and hMSH6-L1354Q missense mutations were identified in two separate families, both suspected of LS but not fulfilling the criteria
Summary
Lynch Syndrome (LS), called hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant disorder that is characterized by early onset cancer of the colorectum and endometrium. It confers an increased risk for cancers of the ovary, small intestine, stomach, ureter, renal pelvis, brain and sebaceous glands [1]. The majority of LS cases is caused by inherited mutations in the DNA mismatch repair (MMR) genes MLH1 and MSH2 (70-80% of all LSassociated colorectal cancer (CRC) cases). Mutations in the MMR genes MSH6 and PMS2 account for the remaining 20-30% of LS-associated tumors [2,3]. MMR gene mutation carriers generally have an up to 10-fold increased lifetime risk of developing CRC (70-80%) and endometrial cancer (40-60%) compared to the general population [4]
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