Mismatch repair genes in Lynch syndrome: a review

Abstract

Lynch syndrome represents 1-7% of all cases of colorectal cancer and is an autosomal-dominant inherited cancer predisposition syndrome caused by germline mutations in deoxyribonucleic acid (DNA) mismatch repair genes. Since the discovery of the major human genes with DNA mismatch repair function, mutations in five of them have been correlated with susceptibility to Lynch syndrome: mutS homolog 2 (MSH2); mutL homolog 1 (MLH1); mutS homolog 6 (MSH6); postmeiotic segregation increased 2 (PMS2); and postmeiotic segregation increased 1 (PMS1). It has been proposed that one additional mismatch repair gene, mutL homolog 3 (MLH3), also plays a role in Lynch syndrome predisposition, but the clinical significance of mutations in this gene is less clear. According to the InSiGHT database (International Society for Gastrointestinal Hereditary Tumors), approximately 500 different LS-associated mismatch repair gene mutations are known, primarily involving MLH1 (50%) and MSH2 (40%), while others account for 10%. Much progress has been made in understanding the molecular basis of Lynch Syndrome. Molecular characterization will be the most accurate way of defining Lynch syndrome and will provide predictive information of greater accuracy regarding the risks of colon and extracolonic cancer and enable optimal cancer surveillance regimens.

Chart 1.. Amsterdam criteria I and II

Figure 1.4. A model for mismatch repair. The top strand of the heteroduplex contains three anomalies that are resolved by the mismatch repair gene system: a base-base mispair, a single-nucleotide insertion loop in the top (primer) strand and a two-nucleotide deletion loop in the bottom (template) strand. All three are targeted by the MSH2/MSH6−MLH1/PMS2 repair complex to give the product shown at the bottom of the figure. In all cases, the repair process is directed by a strand discontinuity (a nick) on the primer strand. The guanine-thymine mispair is corrected to adenine-thymine; the adenine stretch was shortened by one repeat unit and the sequence of cytosine-adenine dinucleotide repeats was extended by one. In the absence of MSH6, the two insertions/deletions are targeted by the MSH2/MSH3-MLH1/PMS2 complex. The putative MSH2/MSH3-MLH1/MLH3 complex is predicted (from yeast studies) to address a subset of insertion/deletion. Figure adapted from Jiricny.