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

• Published in: Clinical cancer research Vol. 25; no. 3; pp. 967 - 976
• Main Authors: Audenet, François, Isharwal, Sumit, Cha, Eugene K., Donoghue, Mark T.A., Drill, Esther N., Ostrovnaya, Irina, Pietzak, Eugene J., Sfakianos, John P., Bagrodia, Aditya, Murugan, Paari, Dalbagni, Guido, Donahue, Timothy F., Rosenberg, Jonathan E., Bajorin, Dean F., Arcila, Maria E., Hechtman, Jaclyn F., Berger, Michael F., Taylor, Barry S., Al-Ahmadie, Hikmat, Iyer, Gopa, Bochner, Bernard H., Coleman, Jonathan A., Solit, David B.
• Format: Journal Article
• Language: English
• Published: United States 01.02.2019
• Subjects: Aged; Biomarkers, Tumor - genetics; Carcinoma, Transitional Cell - genetics; Clone Cells - metabolism; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; Female; Genetic Predisposition to Disease - genetics; Genomics - methods; High-Throughput Nucleotide Sequencing - methods; Humans; Male; Middle Aged; Mutation; Prospective Studies; Receptor, Fibroblast Growth Factor, Type 3 - genetics; Tumor Suppressor Protein p53 - genetics; Urinary Bladder - metabolism; Urinary Bladder - pathology; Urinary Bladder Neoplasms - genetics; Urinary Tract - metabolism; Urinary Tract - pathology
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-2039

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. 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. 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, and were less frequently altered in UTUC (26% vs. 46%, 3% vs. 20%, 8% vs. 19%, respectively; < 0.001), whereas and were more frequently altered (40% vs. 26%, 12% vs. 4%, respectively; < 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 and . Comparison of UCB with corresponding UTUC tumors from the same patient supports their clonal relatedness. 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.