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.

Molecular signaling mechanisms of apoptosis in hereditary non-polyposis colorectal cancer

“…MLH1 and MSH2 are nuclear proteins with 756 and 934 amino acids that respectively encode proteins of approximately 80 KDa and 100 KDa. The MLH1 gene is located on chromosome 3p21 with nineteen exons, while MSH2 gene is on chromosome 2p16 with sixteen exons [37] .…”

Muir-Torre Syndrome: case report and molecular characterization

“…7,11 This syndrome has also been associated with mutations in the MYH gene, which is inherited in an autosomal recessive Lynch syndrome accounts for approximately 3% of the incidence of colon cancer worldwide, and can also present with cancer of the urogenital tract, stomach, small bowel, brain and hepatobiliary tract. 5,6 It is caused by germline mutations in genes of the mismatch repair system, mainly hMSH2 and hMLH1. Molecularly, interferon has been used to prevent some of the cutaneous neoplasms that have been described.…”

Phenotypic Heterogeneity by Germline Mismatch Repair Gene Defect in Lynch Syndrome Patients

“…12,14 Data from the International Society for Gastrointestinal and Hereditary Tumours (InSiGHT) relative to the year of 2012 registered a frequency of LS-associated mutations of 42% for MLH1, 33% for MSH2, 18% for MSH6 and 8%…”

“…[6][7][8] Therefore, 36,000 -60,000 of CRCs worldwide are associated with LS, 9 with an average age of onset of 45 years. 10,11 This is a dominantly inherited disorder with 85% of penetrance, 12 featuring germline mutations in at least one of the DNA mismatch repair (MMR) genes.…”

“…40,41 Those are patients expected to have less risk of developing CRC and older age of onset. 40,42 Considering particularly MSH6 patients, the penetrance of their mutation is thought to be lower 12 and also they do not show an ubiquitous MSI profile. 43 For these patients, the incidence of CRC is lower 42 (particularly in women: 10% -30% risk of CRC; in men it is higher: 22% -69% risk of CRC) and the age of onset for CRC is higher (most frequently between 50 -63 32 and with a mean age of diagnosis of 54 years old) 12 than that of patients with the previous enounced mutations.…”