@article{38c9b1af36264c80967f90b08584c2d4,
title = "Genomic Characterization of Upper Tract Urothelial Carcinoma",
abstract = "Background Despite a similar histologic appearance, upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) tumors have distinct epidemiologic and clinicopathologic differences. Objective To investigate whether the differences between UTUC and UCB result from intrinsic biological diversity. Design, setting, and participants Tumor and germline DNA from patients with UTUC (n = 83) and UCB (n = 102) were analyzed using a custom next-generation sequencing assay to identify somatic mutations and copy number alterations in 300 cancer-associated genes. Outcome measurements and statistical analysis We described co-mutation patterns and copy number alterations in UTUC. We also compared mutation frequencies in high-grade UTUC (n = 59) and high-grade UCB (n = 102). Results and limitations Comparison of high-grade UTUC and UCB revealed significant differences in the prevalence of somatic alterations. Genes altered more commonly in high-grade UTUC included FGFR3 (35.6% vs 21.6%; p = 0.065), HRAS (13.6% vs 1.0%; p = 0.001), and CDKN2B (15.3% vs 3.9%; p = 0.016). Genes less frequently mutated in high-grade UTUC included TP53 (25.4% vs 57.8%; p < 0.001), RB1 (0.0% vs 18.6%; p < 0.001), and ARID1A (13.6% vs 27.5%; p = 0.050). Because our assay was restricted to genomic alterations in a targeted panel, rare mutations and epigenetic changes were not analyzed. Conclusions High-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB. However, there were significant differences in the prevalence of several recurrently mutated genes including HRAS, TP53, and RB1. As relevant targeted inhibitors are being developed and tested, these results may have important implications for the site-specific management of patients with urothelial carcinoma. Patient summary Comparison of next-generation sequencing of upper tract urothelial carcinoma (UTUC) with urothelial bladder cancer identified that similar mutations were present in both cancer types but at different frequencies, indicating a potential need for unique management strategies. UTUC tumors were found to have a high rate of mutations that could be targeted with novel therapies.",
keywords = "Bladder cancer, Genomics, Targeted therapy, Upper tract urothelial carcinoma",
author = "Sfakianos, {John P.} and Cha, {Eugene K.} and Gopa Iyer and Scott, {Sasinya N.} and Zabor, {Emily C.} and Shah, {Ronak H.} and Qinghu Ren and Aditya Bagrodia and Kim, {Philip H.} and Hakimi, {A. Ari} and Irina Ostrovnaya and Ricardo Ramirez and Hanrahan, {Aphrothiti J.} and Desai, {Neil B.} and Arony Sun and Patrizia Pinciroli and Rosenberg, {Jonathan E.} and Guido Dalbagni and Nikolaus Schultz and Bajorin, {Dean F.} and Reuter, {Victor E.} and Berger, {Michael F.} and Bochner, {Bernard H.} and Al-Ahmadie, {Hikmat A.} and Solit, {David B.} and Coleman, {Jonathan A.}",
note = "Funding Information: Eugene K. Cha certifies that all conflicts of interest,including specific financial interests and relationships and affiliationsrelevant to the subject matter or materials discussed in the manuscript(eg, employment/affiliation, grants or funding, consultancies, honoraria,stock ownership or options, expert testimony, royalties, or patents filed,received, or pending), are the following: None. Funding/Support and role of the sponsor: This work was supported bythe National Institutes of Health, the Michael and Zena Wiener forTherapeutics Program in Bladder Cancer, Cycle for Survival, theThompson Foundation, and the Urology Care Foundation ResearchScholars Program (design and conduct of the study, and collection,analysis, and interpretation of the data). John P. Sfakianos was a researchfellow in urologic oncology supported by NIH T32-CA82088. Acknowledgments: We thank Kety Huberman, Igor Dolgalev, OlgaAminova, Sabrena Thomas, and Nathalie Lallier from the Geoffrey BeeneTranslational Oncology Core for assistance with the MiSeq studies;Nancy Bouvier fromthe Center for Molecular Oncology for assistance withMSK-IMPACT; and Maria Corazon Mariano, Katrina Allen, Priscilla McNeil,Daniel Navarrete, Anas Idelbi, and Anupama Gandhi from the PathologyCore for assistance with tissue collection and processing. Funding Information: Funding/Support and role of the sponsor: This work was supported by the National Institutes of Health, the Michael and Zena Wiener for Therapeutics Program in Bladder Cancer, Cycle for Survival, the Thompson Foundation, and the Urology Care Foundation Research Scholars Program (design and conduct of the study, and collection, analysis, and interpretation of the data). John P. Sfakianos was a research fellow in urologic oncology supported by NIH T32-CA82088. Publisher Copyright: {\textcopyright} 2015 European Association of Urology.",
year = "2015",
doi = "10.1016/j.eururo.2015.07.039",
language = "English (US)",
volume = "68",
pages = "970--977",
journal = "European urology",
issn = "0302-2838",
publisher = "Elsevier",
number = "6",
}