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Upper tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Although large cohorts have illustrated spectrum of germline mutations, landscape of somatic alterations has not been revealed in Chinese patients with UTUC.

This study involved 122 Chinese patients with UTUC. Paired tumor and germline DNA was sequenced to elucidate somatic mutation landscape, using targeted next-generation sequencing panel covering 520 cancer-related genes. We correlated specific gene mutations with clinicopathologic features, compared mutational signatures with previously reported data in other populations, and explored the similarities and differences in mutational signatures of UTUC originated from renal pelvis or ureter.

Somatic mutations were detected in 120/122 (98.4%) patients using this 520-gene panel sequencing. The top-ranking altered genes in Chinese patients with UTUC were KMT2D (48.4%), TERT promoter (46.7%), FGFR3 (41.0%), and TP53 (37.7%). Renal pelvis tumors had significantly higher TERT promoter (60.5% v 30.8%; P < .05) and CDKN2A (29.6% v 7.7%; P < .05) alteration frequency, while TP53 (56.4% v 30.9%; P < .05) and KMT2D (76.9% v 35.8%; P < .001) gene mutations were enriched in patients with ureteral tumors. By comparing the mutational spectrum with Japanese and Western populations, we identified the unique genetic characteristics and potential precision treatment targets of the Chinese UTUC population. Finally, we found that patients with TP53/MDM2-mutant subtype or triple-negative subtype had significantly worse progression-free survival than other subtypes.

This study elucidated genomic landscape of Chinese patients with UTUC and revealed similarity and disparity of genomic alterations with other populations. Our research lays the foundation for understanding UTUC in China and designing precise diagnosis and treatment.