Heritable epigenetic mutation of MLHI in a mother and daughter with Lynch syndrome

Background Lynch syndrome is a hereditary predisposition to colorectal and endometrial cancers, in addition to cancers of the stomach, ovary, upper urinary tract, small bowel, hepatobiliary tract, skin and brain. Lynch syndrome is caused by defects in DNA mismatch repair (MMR), and germline mutations in MLHl, MSH2, MSH6 and PMS2 as well as high levels of tumor microsatellite instability (MSI) and loss of MMR protein expression are frequently found. MMR deficiency due to loss of MLH1 in tumor tissue may also be due to gene silencing resulting from hypermethylation of the MLH1 promoter, which is found in 15% of sporadic colorectal and endometrial cancers, and as the second “hit” in some individuals with germline mutations in MLH1. Recently, epigenetic silencing of MLH1 in normal body cells has been proposed as a novel cause of predisposition to Lynch syndrome associated tumors. Twenty five cases of hypermethylation of the MLH1 promoter in peripheral blood (MLH1 epimutation) of individuals with young onset colorectal cancer and/or endometrial cancer have been reported. The heritability of MLH1 epimutation is still under investigation.