MLH1 (MIM:120436) is a mismatch repair protein that, together with PMS2 (MIM:600259), facilitates binding of other protein effectors of DNA repair.1 Inactivation of both alleles of MLH1 in tumor typically leads to microsatellite instability (MSI) in its target genes following DNA polymerase slippage errors, 2-3 as well as to abnormal immunohistochemical staining (IHC) for MLH1 and/or PMS2.
In general, MSI is observed in approximately 90% of cases of hereditary non-polyposis colorectal cancer (HNPCC) and in about 15% of sporadic colorectal cancer cases.4 MSI is usually a consequence of somatic MLH1 promoter methylation.5 Therefore, as with BRAF V600E mutation, with which it is strongly correlated, MLH1 promoter methylation testing helps to identify sporadic rather than hereditary microsatellite-unstable tumors,2,6 and, where indicated, guide further testing. A recent study of familial colorectal tumors with MSI and/or loss of mismatch repair protein expression demonstrated that MLH1 promoter hypermethylation screening on HNPCC tumor biopsies outperforms BRAF mutation analysis in both analytical performance and cost-effectiveness.4
It is important to note that the analysis of the results of MLH1 promoter methylation requires careful consideration of family and clinical histories. One reason is that up to 1% of HNPCC cases appear to be caused by constitutional MLH1 epimutation.5,7 Secondly, MLH1 promoter hypermethylation may represent a second hit, co-occurring with a germline mutation.4,8 Therefore, a diagnosis of HNPCC cannot be eliminated on the basis of a positive MLH1 promoter hypermethylation result alone.*
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