Genomic characterization of upper tract urothelial carcinoma Journal Article

Authors: Sfakianos, J. P.; Cha, E. K.; Iyer, G.; Scott, S. N.; Zabor, E. C.; Shah, R. H.; Ren, Q.; Bagrodia, A.; Kim, P. H.; Hakimi, A. A.; Ostrovnaya, I.; Ramirez, R.; Hanrahan, A. J.; Desai, N. B.; Sun, A.; Pinciroli, P.; Rosenberg, J. E.; Dalbagni, G.; Schultz, N.; Bajorin, D. F.; Reuter, V. E.; Berger, M. F.; Bochner, B. H.; Al-Ahmadie, H. A.; Solit, D. B.; Coleman, J. A.
Article 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. © 2015 European Association of Urology.
Keywords: bladder cancer; genomics; targeted therapy; upper tract urothelial carcinoma
Journal Title: European Urology
Volume: 68
Issue: 6
ISSN: 0302-2838
Publisher: Elsevier Science, Inc.  
Date Published: 2015-12-01
Start Page: 970
End Page: 977
Language: English
DOI: 10.1016/j.eururo.2015.07.039
PROVIDER: scopus
PUBMED: 26278805
PMCID: PMC4675454
Notes: Article -- Export Date: 3 February 2016 -- Source: Scopus
Citation Impact
MSK Authors
  1. Jonathan Coleman
    218 Coleman
  2. Dean Bajorin
    505 Bajorin
  3. Guido Dalbagni
    270 Dalbagni
  4. David Solit
    537 Solit
  5. Gopakumar Vasudeva Iyer
    165 Iyer
  6. Emily Craig Zabor
    160 Zabor
  7. Neil B Desai
    35 Desai
  8. Bernard Bochner
    357 Bochner
  9. Michael Forman Berger
    495 Berger
  10. Victor Reuter
    1068 Reuter
  11. Philip Hyunwoo Kim
    39 Kim
  12. Nikolaus D Schultz
    258 Schultz
  13. Jonathan Eric Rosenberg
    294 Rosenberg
  14. Abraham Ari Hakimi
    180 Hakimi
  15. Arony Jessica Sun
    6 Sun
  16. Ronak Hasmukh Shah
    46 Shah
  17. Sasinya Neka Scott
    69 Scott
  18. Qinghu Ren
    13 Ren
  19. Ricardo   Ramirez
    19 Ramirez
  20. Eugene K. Cha
    64 Cha