Genomic characterization of upper urinary tract urothelial carcinoma and clonal evolution of intravesical recurrences

Background and ObjectivePatients with upper urinary tract urothelial carcinoma (UTUC) undergoing radical surgery are at high risk of developing intravesical recurrences (IVR). The biology of IVR after surgery for UTUC is poorly understood, and urine markers to replace cystoscopic surveillance of the bladder are lacking. Here, we characterized the genomic landscape of UTUC and paired IVR to discover therapeutic targets and identify diagnostic markers for IVR. MethodsWe performed targeted next-generation DNA-sequencing of 571 genes in a cohort of 276 retrospectively and 138 prospectively enrolled UTUC patients who received radical surgery. Clonality and evolution were assessed in 79 paired UTUC-IVR cases. Key Findings and LimitationsMutations in TERT (72%) and FGFR3 (50%) were highly prevalent in UTUC, while mutations in KMT2C were associated with reduced risk of IVR. The mutually exclusive mutational profile of UTUC revealed five genomic subtypes with distinct clinicopathological and molecular characteristics, but none were associated with elevated IVR risk. Clonal evolution of paired UTUC-IVR occurred in 92% of cases via four evolutionary paths, with FGFR3 as a key driver in the largest path (36%). Additionally, hotspot mutations in the TERT promoter, and FGFR3 and HRAS genes were identified as potential markers for noninvasive surveillance by urine testing. Limitations include cohort heterogeneity and the selected gene-targeted sequencing approach. Conclusions and Clinical ImplicationsThe high FGFR3 mutation rate in UTUC and its association with IVR development support anti-FGFR targeted therapy to reduce IVR risk. The clonal relationship between UTUC and IVR underscores the potential for patient-friendly noninvasive urine tests for surveillance after radical surgery. SummaryUpper urinary tract urothelial carcinoma (UTUC) is a rare cancer with a high recurrence rate after surgery. We found that the FGFR3 gene is a potential therapeutic target to reduce the risk of recurrence, while recurrent mutations in TERT, FGFR3 and HRAS could serve as potential markers for noninvasive surveillance by urine testing after surgery for UTUC.