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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 [
5–
7]. 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.....