林奇综合征是一种由错配修复基因突变引起的常染色体显性遗传病，与多种肿瘤类型的发生有关，特别是结直肠癌、子宫内膜癌和上尿路尿路上皮癌。在这项研究中，我们介绍了一名被诊断患有上尿路尿路上皮癌的年轻患者的病例，该患者因有多种恶性肿瘤的家族史而引人注目。通过遗传分析，我们验证了该家族中林奇综合征的存在，并利用 NGS 技术检测到了新的变异体 MSH2 p.A604D 和 TSC2 p.C738Y。随后，我们进行了验证实验来评估 MSH2 和 TSC2 变体的致病性。我们发现，MSH2 变异可导致 MSH2 表达减少、错配修复功能受损，并诱导尿路上皮癌对顺铂产生耐药性。此外，我们证实了已识别的 TSC2 变异对尿路上皮癌的促进作用，包括增殖、侵袭和迁移。值得注意的是，我们发现MSH2 p.A604D变异体和TSC2 p.C738Y变异体协同增强尿路上皮癌的发生。版权所有©2023。由Elsevier Inc.出版。

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.Copyright © 2023. Published by Elsevier Inc.