Diagnostics of Mutations in MMR/EPCAM Genes and Their Role in the Treatment and Care of Patients with Lynch Syndrome

Abstract

Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a disorder caused by an autosomal dominant heterozygous germline mutation in one of the DNA mismatch repair (MMR) genes. Individuals with LS are at an increased risk of developing colorectal and extracolonic cancers, such as endometrial, small bowel, or ovarian. In this review, the mutations involved with LS and their diagnostic methods are described and compared, as are their current uses in clinical decision making. Nowadays, LS diagnosis is based on a review of family medical history, and when necessary, microsatellite instability (MSI) or/and immunohistochemistry (IHC) analyses should be performed. In the case of a lack of MMR protein expression (dMMR) or MSI-H (MSI-High) detection in tumor tissue, molecular genetic testing can be undertaken. More and more genetic testing for LS is based mainly on next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA), which provide better and quicker information about the molecular profile of patients as well as individuals at risk. Testing based on these two methods should be the standard and commonly used. The identification of individuals with mutations provides opportunities for the detection of cancer at an early stage as well as the introduction of proper, more effective treatment, which will result in increased patient survival and reduced costs of medical care.

Overview on population screening for carriers with germline mutations in mismatch repair (MMR) genes in China

“…LS patients and mutation carriers were diagnosed by MMR gene testing from MLH1 -deficient cases with MLH1 unmethylation, MLH1 -deficient cases with wild-type BRAF CRC, and other protein deficiency cases [ 4 ]. Additionally, MLH1 promoter-methylated CRC was also detected among individuals with family history of cancer and MLH1 splicing mutant [ 4 , 32 ], indicating that family history of LS-RC is an important factor to avoid missing suspected case. Next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) are also promising approaches for gene testing, which can provide better and faster gene characteristics for cancer patients and high-risk individuals [ 6 , 33 , 34 ].…”

Tumour-Agnostic Therapy for Pancreatic Cancer and Biliary Tract Cancer

“…Among the MMR genes, mutL homolog 1(MLH1), mutS homolog 2 (MSH2), MSH6, and PMS2 are reportedly involved in germline pathogenic mutations in Lynch syndrome [55]. Additionally, since epithelial cell adhesion molecule (EPCAM) is located adjacent and upstream to MSH2 and deletion of EPCAM causes decreased expression of MSH2, deletion of the germline EPCAM leads to the development of Lynch syndrome [56]. Furthermore, abnormalities in the functions of MMR-related genes other than those of the abovementioned genes may also result in Lynch syndrome [57].…”

Lynch Syndrome: Its Impact on Urothelial Carcinoma

“…Any defect in these proteins results in an inactive DNA repair process, which increases pathogenic alteration rates in genes of the cell growth cycle, leading to defects in tumor suppressor genes and oncogenes, followed by an elevated cancer risk [ 22 ]. Insufficient MMR and subsequent variation in the number of nucleotides in a microsatellite region, defined as small repetitive DNA sequences, is referred to as microsatellite instability (MSI), which is present in approximately 95% for of all tumors associated with LS [ 15 ].…”