1. Academic Validation
  2. Novel MSH2 and TSC2 variants in a Chinese family with Lynch syndrome and their synergistic impact in urothelial carcinoma

Novel MSH2 and TSC2 variants in a Chinese family with Lynch syndrome and their synergistic impact in urothelial carcinoma

  • Transl Res. 2023 Oct 31:S1931-5244(23)00179-2. doi: 10.1016/j.trsl.2023.10.006.
Mingyang Li 1 Xingjian Yan 2 He Liu 1 Wenhao Miao 1 Wenbo Wu 1 Yuyang Zhao 3 Chungang Wang 4 Haitao Liu 5
Affiliations

Affiliations

  • 1 Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China.
  • 2 Department of Urology, The First Hospital of Jilin University, Changchun, Jilin 130021, Chin.
  • 3 Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China. Electronic address: drzhaoyuyang@aliyun.com.
  • 4 Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China. Electronic address: chungang.wang@shgh.cn.
  • 5 Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China. Electronic address: haitaoliu@shgn.cn.
Abstract

Lynch syndrome, an autosomal dominant hereditary disease arising from mutations in mismatch repair genes, is linked to the development of multiple tumor types, notably colorectal Cancer, endometrial carcinoma and upper urinary tract urothelial carcinoma. In this study, we present the case of a young patient diagnosed with upper urinary tract urothelial carcinoma, notable for a familial history of diverse malignancies. By employing genetic analysis, we verified the presence of Lynch syndrome within the family and detected novel variants, MSH2 p.A604D and TSC2 p.C738Y, utilizing NGS technology. Subsequently, we conducted validation experiments to assess the pathogenicity of the MSH2 and TSC2 variants. We illustrated that the MSH2 variant can result in diminished MSH2 expression, compromised mismatch repair function, and induce resistance to cisplatin in urothelial carcinoma. Furthermore, we substantiated the promotional impact of the identified TSC2 variant on urothelial carcinoma, encompassing proliferation, invasion, and migration. Significantly, we found that the MSH2 p.A604D variant and TSC2 p.C738Y variant synergistically enhance the promotion of urothelial carcinoma.

Keywords

Gene variant; Lynch syndrome; Synergistic function; Urothelial carcinoma.

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