MSH6 syndrome

The MSH6 gene in collaboration with MSH2, MLH1, MSH3, PMS1 and PMS2 genes is involved in one of the systems repairing the errors that arise during DNA replication, called the “methyl directed mismatch repair” system [1-3]. hMLH1 and hMSH2 mutations give rise most frequently to the classical Lynch syndrome (HNPCC) [4-6]. hMSH6 mutations often occur in clinically less typical HNPCC families, that do not fulfil the Amsterdam criteria [7-11]. So far more than 200 families with germline hMSH6 mutation have been described (www.med.ca/MMRvariants). Characteristic features of families with hMSH6 mutation are: • higher risk for colorectal cancer (~70% for men and ~30% for females), endometrial cancer (~70%) and also for ovarian, upper urinary tract, stomach and breast cancer [12], • higher incidence of extracolonic cancers, when compared with HNPCC families [13], • later age at onset of cancers, e.g. for colorectal cancer the mean age at diagnosis is ~56 years, for endometrial cancer ~54 years and for ovarian cancer ~49 years [12, 13], • frequent left-sided localization of colorectal cancer [9]. The prevalence of hMSH6 constitutional mutations in families that fulfil the Amsterdam criteria is about 5-10% [8, 9]. Because the frequency of hMSH6 mutations in other groups is not precisely determined, we recommend the following diagnostic procedure for hMSH6 mutation detection: • selection of families with colorectal, endometrial, ovarian, urinary tract and/or stomach, breast cancer aggregation, • immunohistochemical analysis (IHC) of hMSH6 protein expression in tumour colorectal or endometrial tissue [14-16], • in cases of hMSH6-negative tumours, DHPLC/ sequencing of the coding regions of the hMSH6 gene. Among the reported hMSH6 mutations about 30 are recurrent, i.e. they are detected in more than one family [17-19]. Probably in the near future diagnostic tests will be described to allow cheap, simple and fast detection of mutations showing a “founder effect” characteristic for particular ethnic groups.