A Hereditable Mutation of MSH2 Gene Associated with Lynch Syndrome in a Five Generation Chinese Family
Received 9 July 2019
Accepted for publication 24 December 2019
Published 27 February 2020 Volume 2020:12 Pages 1469—1482
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 2
Editor who approved publication: Dr Eileen O'Reilly
Wei-Hua Shao,1– 4,* Cheng-Yu Wang,4,5,* Lei-Yun Wang,1– 4 Fan Xiao,1– 4 De-Sheng Xiao,6 Hao Yang,4,5 Xue-Ying Long,7 Le Zhang,8 Heng-Gui Luo,9 Ji-Ye Yin,1– 4 Wei Wu4,5
1Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410078, People’s Republic of China; 2Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, People’s Republic of China; 3Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, People’s Republic of China; 4Department of Geratic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People’s Republic of China; 5National Clinical Research Center for Geriatric Disorders, Changsha, Hunan 410008, People’s Republic of China; 6Department of Pathology, Xiangya Hospital/School of Basic Medicine, Central South University, Changsha 410078, Hunan, People’s Republic of China; 7Department of Radiology, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of China; 8Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 9Department of General Surgery, The Central Hospital of Xiangtan City, Xiangtan, Hunan, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Wei Wu
Department of Geratic Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha 410008, Hunan, People’s Republic of China
Tel +86 731 89753053
Purpose: 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.
Keywords: Lynch syndrome, genetic variation, mismatch repair gene, MSH2, chemotherapy resistance
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