(focus on MSH6) Functional Analysis in Mouse Embryonic Stem Cells Reveals Wild-Type Activity for Three Msh6 Variants Found in Suspected Lynch Syndrome Patients Ovarian Cancer and Us OVARIAN CANCER and US Ovarian Cancer and Us

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Sunday, October 27, 2013

(focus on MSH6) Functional Analysis in Mouse Embryonic Stem Cells Reveals Wild-Type Activity for Three Msh6 Variants Found in Suspected Lynch Syndrome Patients



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Introduction

Lynch Syndrome (LS), also 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 furthermore confers an increased risk for cancers of the ovary, small intestine, stomach, ureter, renal pelvis, brain and sebaceous glands [1]. Tumors often show a high rate of microsatellite instability (MSI). The majority of LS cases is caused by inherited mutations in the DNA mismatch repair (MMR) genes MLH1 and MSH2 (70-80% of all LS-associated 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].
In contrast to families carrying MLH1 and MSH2 mutations, families carrying mutations in MSH6 often do not fulfill the criteria for LS diagnosis. Tumors in MSH6 mutation carriers frequently show no or low MSI and the observed instability is generally restricted to mononucleotide markers [57]. When compared to MLH1 and MSH2 mutation carriers, the age of onset is generally later for MSH6 mutations carriers (approximately 10 years) and they have a lower risk for developing CRC [2,3]. There are reports of increased frequency of endometrial cancer in MSH6 mutation carriers versus MSH2 mutation carriers [8]; however, two large studies found no difference [2] or even a decreased [3] endometrial cancer incidence in patients carrying a mutation in MSH6.....



 

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