Abstract
Lynch syndrome (LS) predisposes to a spectrum of cancers and increases the lifetime risk of developing colorectal- or endometrial cancer to over 50%. Lynch syndrome is dominantly inherited and is caused by defects in DNA mismatch-repair genes MLH1, MSH2, MSH6 or PMS2, with the vast majority detected in MLH1 and MSH2. Recurrent LS-associated variants observed in apparently unrelated individuals, have either arisen de novo in different families due to mutation hotspots, or are inherited from a founder (a common ancestor) that lived several generations back. There are variants that recur in some populations while also acting as founders in other ethnic groups. Testing for founder mutations can facilitate molecular diagnosis of Lynch Syndrome more efficiently and more cost effective than screening for all possible mutations. Here we report a study of the missense mutation MLH1 c.2059C > T (p.Arg687Trp), a potential founder mutation identified in eight Swedish families and one Finnish family with Swedish ancestors. Haplotype analysis confirmed that the Finnish and Swedish families shared a haplotype of between 0.9 and 2.8 Mb. While MLH1 c.2059C > T exists worldwide, the Swedish haplotype was not found among mutation carriers from Germany or France, which indicates a common founder in the Swedish population. The geographic distribution of MLH1 c.2059C > T in Sweden suggests a single, ancient mutational event in the northern part of Sweden.
Highlights
Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome worldwide, representing 2–4% of the total colorectal cancer burden [1, 2]
The syndrome is caused by inherited mutations in any of the five MMR genes MLH1, MSH2, MSH6, EPCAM or PMS2
A number of pathogenic founder mutations have been described in those genes, which are shared by apparently unrelated families that inherited them from a common ancestor
Summary
Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome worldwide, representing 2–4% of the total colorectal cancer burden [1, 2]. Among individuals with a cancer diagnosis at young age the proportion is much higher. LS has an autosomal dominant pattern of inheritance and is caused by germline mutations in any of the DNA mismatch-repair genes MLH1, MSH2, MSH6, PMS2 and EPCAM [4]. Because of incomplete penetrance and variable age of cancer development not all mutation carriers develop cancer. There is up to 70% lifetime risk to come down with early onset colorectal- or endometrial cancer, with the characteristic accelerated development from adenoma to carcinoma [3]. To date just above 3000 sequence variants have been reported for MLH1, MSH2, MSH6 and PMS2
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