Clonal Relatedness and Mutational Differences between Upper Tract and Bladder Urothelial Carcinoma

Abstract

Purpose: To investigate genomic differences between urothelial carcinomas of the upper tract (UTUC) and bladder (UCB), with a focus on defining the clonal relatedness of temporally distinct tumors.Experimental Design: We prospectively sequenced tumors and matched germline DNA using targeted next-generation sequencing methods. The cohort included 195 UTUC patients and 454 UCB patients. For a subgroup of 29 patients with UTUC and a history of a subsequent UCB, both tumors were analyzed to assess their clonal relatedness.Results: With the progression to higher UTUC clinical state, there were fewer alterations in the RTK/RAS pathway but more alterations in TP53/MDM2. Compared with UCB, TP53, RB1, and ERBB2 were less frequently altered in UTUC (26% vs. 46%, 3% vs. 20%, 8% vs. 19%, respectively; Q < 0.001), whereas FGFR3 and HRAS were more frequently altered (40% vs. 26%, 12% vs. 4%, respectively; Q < 0.001). On the basis of an integrated analysis of tumor mutational burden, MSIsensor score and mutational signature, 7.2% of UTUC tumors were classified as MSI-high/MMR-deficient (MSI-H/dMMR). The risk of bladder recurrence after UTUC was significantly associated with mutations in FGFR3, KDM6A, CCND1, and TP53. Comparison of UCB with corresponding UTUC tumors from the same patient supports their clonal relatedness.Conclusions: UTUC and UCB exhibit significant differences in the prevalence of common genomic alterations. In individual patients with a history of both tumors, UCB and UTUC were always clonally related. Genomic characterization of UTUC provides information regarding the risk of bladder recurrence and can identify tumors associated with Lynch syndrome.

Molecular changes during progression from nonmuscle invasive to advanced urothelial carcinoma

“…Taken together, our data is fully compatible with a model in which a clonal premalignant field is the precursor of semi‐independent recurrences. However, recent work has demonstrated the similarity between upper urinary tract urothelial cancer and bladder recurrences suggesting that recurrence due to dissemination may occur in this particular context . By introducing the concept of molecular subtypes, we contextualize also the well‐established two‐pathway model for luminal‐like tumors.…”

“…However, recent work has demonstrated the similarity between upper urinary tract urothelial cancer and bladder recurrences suggesting that recurrence due to dissemination may occur in this particular context. 51 By introducing the concept of molecular subtypes, we contextualize also the well-established two-pathway model for luminallike tumors. Finally, we add to the model two fundamentally different modes of progression: For most patients, progression occurs without any change in molecular subtype.…”

Patient-Derived Xenograft Models in Urological Malignancies: Urothelial Cell Carcinoma and Renal Cell Carcinoma

“…To date, only six attempts at PDX creation from upper tract urothelial carcinoma (UTUC) have been reported with limited establishment and characterization [36]. As the genomic landscape of urothelial carcinoma is further elucidated, key differences have been identified in tumors of upper tract origin, differentiating them from lower urinary tract bladder cancers with potential biological and clinical implications [37,38]. Further work is needed to develop such PDX models.…”

Infigratinib in upper tract urothelial carcinoma versus urothelial carcinoma of the bladder and its association with comprehensive genomic profiling and/or cell‐free DNA results

“…In what to our knowledge is the largest comparison of UTUC versus UCB genomics published to date, Audenet et al assessed 195 patients with UTUC and 454 with UCB. In their study, FGFR3 and HRAS were more frequently altered in UTUC compared with UCB (40% vs 25% and 12% vs 4%, respectively) …”