<p>A Hereditable Mutation of MSH2 Gene Associated with Lynch Syndrome in a Five Generation Chinese Family</p>

Abstract

In order to clarify which variants of the MMR gene could provide current "healthy" members in affected families a more accurate risk assessment or predictive testing. Patients and Methods: One family, which meets the criteria according to both Amsterdam I/II and Bethesda guidelines, is reported in this study. The proband and some relatives of the patient have been investigated for whole genome sequencing, microsatellite instability, immunohistochemical MMR protein staining and verified by Sanger sequencing. Results: A heterozygous insertion of uncertain significance (c.420dup, p.Met141Tyrfs) in MSH2 gene was found in proband (III-16) and part of His relatives. The variant was associated with a lack of expression of MSH2 protein (MMR deficient) and high microsatellite instability analysis (MSI) status in tumor tissues of LS patients. In addition, we found that the variant could affect the expression of MSH2 and the response to chemotherapy drugs in vitro. Conclusion: We identified an insertion mutation (rs1114167810, c.420dup, p.Met141Tyrfs) in MSH2 in LS using whole genome-wide sequencing (WGS). We further confirmed that this mutation plays an important role in LS patients of this pedigree based on in vivo and vitro study.

The MSH2 c.793-1G>A variant disrupts normal splicing and is associated with Lynch syndrome

“…Genomic DNA was isolated from blood samples of III-14 and III-15 and tested for MSI. A five-marker panel including two mononucleotide repeats (BAT25 and BAT26) and three dinucleotide repeats (D2S123, D5S346, and D17S250), which is recommended by the National Cancer Institute (NCI) Workshop on MSI for Cancer Detection and Familial Predisposition, was used as previously described ( 25 ). Oligonucleotide primers were fluorescently labeled, and PCR products were evaluated using the 3500DX Genetic Analyzer.…”

Identification of SNPs in hMSH3/MSH6 interaction domain affecting the structure and function of MSH2 protein

“…Several polymorphism studies have shown the strong association of SNPs toward the susceptibility of cancer. 9,10 Elek et al 11 have recently demonstrated that SNP rs34944508 influences MGAT5 expression, which catalyzes the addition of Nacetylglucosamine (GlcNAc) in β [1][2][3][4][5][6] linkage to mannose of N-linked oligosaccharide, which is a characteristic of invasive lung malignancies. A study conducted by Slovakova et al 12 on promoter polymorphisms for selected MMR genes viz MSH2 (rs2303425) has evaluated the risk of cancer development in both dominant and recessive genetic models and demonstrated that polymorphism of MMR genes MSH2 is associated with a risk of developing sporadic cancer and hereditary tumors in Slovak people.…”

“…MutS Homolog 2 (MSH2) protein plays an essential role in DNA repair and is associated with different cancer such as hereditary nonpolyposis colorectal cancer (HNPCC), Lynch syndrome, and lung cancer 1–3 . MSH2 comprises two interaction domains (MSH3/MSH6 and MSH2/PMS2) and one DNA binding domain, which are present in two different locations on the gene (Figure 1).…”

“…Elek et al 11 . have recently demonstrated that SNP rs34944508 influences MGAT5 expression, which catalyzes the addition of N‐acetylglucosamine (GlcNAc) in β 1–6 linkage to mannose of N‐linked oligosaccharide, which is a characteristic of invasive lung malignancies. A study conducted by Slovakova et al 12 .…”

Whole-genome sequencing identified novel mutations in a Chinese family with lynch syndrome

“…Lynch syndrome (LS) is an autosomal dominant syndrome linked to a variety of cancers of the colon, endometrium, ovary, and others ( 1 , 2 ). LS is mainly caused by germline and epistatic mutations in the human mismatch repair (MMR) gene ( 3 ).…”