Upper tract urothelial carcinoma (UTUC) accounts for 10% of urothelial carcinomas (UCs) and has a substantial hereditary component. However, the majority of our knowledge of germline spectrum comes from bladder cancer (BCa) data in White populations. Here, we sequence 309 Chinese UTUC cases and identify 71 germline pathogenic/likely pathogenic (P/LP) mutations in 62 patients (20.1%). Compared with White cases, we observe disparities and similarities in inherited mutational profiles. Association analysis reveals that germline P/LP mutations in MSH2, BRCA2, BRCA1, and BRIP1 significantly increase UTUC risk in Chinese populations. Furthermore, germline P/LP mutation in homologous recombination genes indicates poor prognosis for non-metastatic UTUC. Finally, we perform paired sequencing and observe significant correlations between germline mutation patterns and tumor subtypes. This study highlights the importance of genetic testing in patients with UTUC and calls for germline data from various ethnicities to better understand this disease.

Department of Oncology Shanghai Medical College Fudan University Shanghai 200032 China; Department of Pathology Fudan University Shanghai Cancer Center Shanghai 200032 China

Department of Urology Comprehensive Cancer Center Medical University of Vienna 1090 Vienna Austria; Institute for Urology and Reproductive Health Sechenov University 119991 Moscow Russia; Department of Special Surgery Division of Urology Jordan University Hospital the University of Jordan Amman 11942 Jordan; Karl Landsteiner Society Karl Landsteiner Institute of Urology and Andrology Vienna Austria; Department of Urology Weill Cornell Medical College New York NY 10065 USA; Department of Urology University of Texas Southwestern Dallas TX 75390 USA; Department of Urology 2nd Faculty of Medicine Charles University 150 06 Prague Czech Republic; European Association of Urology Research Foundation Arnhem the Netherlands

Department of Urology Fudan University Shanghai Cancer Center Shanghai 200032 China; Department of Oncology Shanghai Medical College Fudan University Shanghai 200032 China

Vita Salute San Raffaele University and IRCCS San Raffaele Hospital Department of Medical Oncology 20132 Milan Italy

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