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


Authors: Audenet, F.; Isharwal, S.; Cha, E. K.; Donoghue, M. T. A.; Drill, E. N.; Ostrovnaya, I.; Pietzak, E. J.; Sfakianos, J. P.; Bagrodia, A.; Murugan, P.; Dalbagni, G.; Donahue, T. F.; Rosenberg, J. E.; Bajorin, D. F.; Arcila, M. E.; Hechtman, J. F.; Berger, M. F.; Taylor, B. S.; Al-Ahmadie, H.; Iyer, G.; Bochner, B. H.; Coleman, J. A.; Solit, D. B.
Article Title: Clonal relatedness and mutational differences between upper tract and bladder urothelial carcinoma
Abstract: 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.
Keywords: tumors; guidelines; colorectal-cancer; signatures; cell carcinomas
Journal Title: Clinical Cancer Research
Volume: 25
Issue: 3
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2019-02-01
Start Page: 967
End Page: 976
Language: English
ACCESSION: WOS:000457395900012
DOI: 10.1158/1078-0432.Ccr-18-2039
PROVIDER: wos
PMCID: PMC6359971
PUBMED: 30352907
Notes: Source: Wos
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MSK Authors
  1. Jonathan Coleman
    184 Coleman
  2. Dean Bajorin
    413 Bajorin
  3. Guido Dalbagni
    251 Dalbagni
  4. David Solit
    435 Solit
  5. Gopakumar Vasudeva Iyer
    126 Iyer
  6. Bernard Bochner
    324 Bochner
  7. Michael Forman Berger
    386 Berger
  8. Maria Eugenia Arcila
    343 Arcila
  9. Barry Stephen Taylor
    141 Taylor
  10. Jonathan Eric Rosenberg
    225 Rosenberg
  11. Timothy Francis Donahue
    17 Donahue
  12. Esther Naomi Drill
    25 Drill
  13. Jaclyn Frances Hechtman
    104 Hechtman
  14. Eugene K. Cha
    58 Cha
  15. Eugene J Pietzak
    20 Pietzak