Abstract
Background: Different genomic characterization in urothelial carcinoma (UC) by site of origin, may imply contrasting therapeutic opportunities and pathogenetic mechanisms. The aim of this study was to investigate whether the differences between upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) result from intrinsic biological diversity.Methods: We prospectively sequenced 118 tumors and matched blood DNA from Chinese UC patients using next-generation sequencing (NGS) techniques, including 45 UTUC and 73 UCB.Results: There were marked disparities in the mutational landscape for UC according to race and site of origin. Signature 22 for exposure to aristolochic acid (AA) and signature 10 for defects in polymerase POLE were only observed in the UTUC cohort. Conversely, signature 6 for defective DNA mismatch repair only existed in the UCB cohort. Compared to UCB, UTUC had higher clonal (p<0.001) and subclonal mutation numbers (p=0.015). TP53, PIK3CA, and FGFR3 mutations may be the driver genes for UTUC, whereas for UCB, the driver gene may be BRCA1. UTUC patients had lower PD-L1 than UCB patients. There was no significant difference in the number of DDR mutations, copy number variation (CNV) counts, tumor mutational burden (TMB) or clinical actionability between UTUC and UCB.Conclusions: UTUC and UCB exhibit significant differences in the prevalence of common genomic landscape and carcinogenesis. Consequently, molecular subtypes differ according to location, and these results may have important implications for the site-specific management of patients with urothelial carcinoma. Mutational signature may be used as a screening tool to assist clinical differential diagnosis between UTUC and UCB.
Comparison of genomic characterization in upper tract urothelial carcinoma and urothelial carcinoma of the bladder