Clonal relatedness and mutational differences between upper tract and bladder urothelial carcinoma

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 to UCB, TP53, RB1and ERBB2were less frequently altered in UTUC (26% vs 46%, 3% vs 20%, 8% vs 19%, respectively; Q<0.001), whereas FGFR3and HRASwere 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, CCND1and TP53 Comparison of UCB to 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.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2018 Oct 23 [Epub ahead of print]

François Audenet, Sumit Isharwal, Eugene K Cha, Mark T A Donoghue, Esther Drill, Irina Ostrovnaya, Eugene J Pietzak, John P Sfakianos, Aditya Bagrodia, Paari Murugan, Guido Dalbagni, Timothy F Donahue, Jonathan E Rosenberg, Dean F Bajorin, Maria E Arcila, Jaclyn F Hechtman, Michael F Berger, Barry S Taylor, Hikmat A Al-Ahmadie, Gopa Iyer, Bernard H Bochner, Jonathan Coleman, David B Solit

Memorial Sloan Kettering Cancer Center ., Department of Surgery, Memorial Sloan Kettering Cancer Center., Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center., Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center., Urology, Icahn School of Medicine at Mount Sinais., Urology, University of Texas Southwestern Medical Center at Dallas., Laboratory Medicine and Pathology, University of Minnesota., Surgery, Memorial Sloan Kettering Cancer Center., Medicine, Memorial Sloan Kettering Cancer Center., Medicine, Weill Cornell Medical College., Memorial Sloan Kettering Cancer Center., Department of Pathology, Memorial Sloan Kettering Cancer Center., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center., Pathology, Memorial Sloan Kettering Cancer Center., Surgery, Urology Service, Memorial Sloan Kettering Cancer Center.

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