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.
Bibliographical noteFunding Information:
This work was supported by NIH R01-CA182587-05, the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Cycle for Survival, and the Thompson Family Foundation.
E.J. Pietzak is a consultant/advisory board member for Merck. J.E. Rosenberg has ownership interests (including patents) at Illumina; reports receiving speakers bureau honoraria from Chugai Pharma; is a consultant/advisory board member for Adicet Bio, Agensys/Astellas, AstraZeneca, Bayer, Fortress Biotech, Lilly, Merck, BioClin Therapeutics, and Sensei Biotherapeutics; reports receiving commercial research grants from Novartis and Roche/Genentech; and reports receiving commercial research support from Astellas, Bayer, Mirati, Roche/ Genentech, and Seattle Genetics. D.F. Bajorin reports receiving speakers bureau honoraria from Merck; is a consultant/advisory board member for AstraZeneca, Eli Lilly, Fidia Farmici, Genentech, Merck, Pfizer, and Urogen; and reports receiving commercial research grants from Merck and Novartis. J.F. Hechtman reports receiving speakers bureau honoraria from Medscape. M.F. Berger is a consultant/advisory board member for Roche. H. Al-Ahmadie is a consultant/ advisory board member for Bristol-Myers Squibb and EMD Serono. G. Iyer is a consultant/advisory board member for Bayer. B.H. Bochner is a consultant/ advisory board member forGenentech. D.B. Solitis aconsultant/advisory board member for Illumina, Loxo Oncology and Pfizer. No potential conflicts of interest were disclosed by the other authors.
© 2018 American Association for Cancer Research.