Differences in genomic profile of high-grade urothelial carcinoma according to tumor location

Objectives: To establish targeted therapies based on the molecular landscape in upper urinary tract urothelial carcinoma (UTUC), we tried to investigate the molecular characteristics of UTUC compared with those of bladder urothelial carcinoma (BLUC) by next-generation sequencing (NGS). Materials and methods: We selected 71 high-grade infiltrating urothelial carcinoma tissue specimens from 33 UTUC and 38 BLUC patients. NGS analysis was performed with the Illumina TruShigt Oncology-500 panel. Results: Both UTUC and BLUC showed similar clinicopathologic characteristics, as well as morphologic similarities. The median tumor mutation burden (TMB) of all cases was 7.8 mutations/Mb. The majority of alterations were missense mutations. TP53 (40/71, 56.3%), KDM6A (30/71, 42.3%), and TERT promoter mutations (23/71, 32.4%) were observed regardless of tumor location. Compared with UTUC, BLUC showed frequent mutations in several genes: ARID1A (P = 0.001), ASXL1 (P = 0.017), ERBB3 (P = 0.005), PRKDC (P = 0.004) and RB1 (P = 0.041). On the contrary, copy number loss of FGFR3 was observed more in UTUC than BLUC (P = 0.018). Also, 6 cases showed oncogenic fusions: 3 cases with FGFR2 fusion in UTUC and 3 cases with FGFR3-TACC3 fusion in BLUC. Conclusion: Despite the small cohort size, we identified genetic differences between UTUC and BLUC in Korean patients by NGS. An understanding of the comprehensive molecular characteristics of UTUC and BLUC may be helpful in detecting candidates for targeted therapy.