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Prognostic significance of BAP1 expression in high-grade upper tract urothelial carcinoma: a multi-institutional study

  • Ahmet M. Aydin
  • Nirmish Singla
  • Vandana Panwar
  • Solomon L. Woldu
  • Yuval Freifeld
  • Christopher G. Wood
  • Jose A. Karam
  • Alon Z. Weizer
  • Jay D. Raman
  • Mesut Remzi
  • Nathalie Rioux-Leclercq
  • Andrea Haitel
  • Marco Roscigno
  • Christian Bolenz
  • Karim Bensalah
  • Mary E. Westerman
  • Arthur I. Sagalowsky
  • Shahrokh F. Shariat
  • Yair Lotan
  • Aditya Bagrodia
  • Payal Kapur
  • Vitaly MargulisEmail author
  • Laura-Maria Krabbe
Original Article
  • 87 Downloads

Abstract

Purpose

To evaluate the prognostic value of BRCA1-associated protein-1 (BAP1) expression in upper tract urothelial carcinoma (UTUC), as BAP1 mutations have been associated with prognostic implications in urologic and non-urologic malignancies.

Methods

We reviewed a multi-institutional cohort of patients who underwent radical nephroureterectomy (RNU) for high-grade UTUC from 1990–2008. Immunohistochemistry (IHC) for BAP1 was performed on tissue microarrays. Staining intensity was graded from 0–3, with BAP1 loss defined as an average intensity of < 1. Clinicopathologic characteristics and oncologic outcomes [recurrencefree (RFS), cancer-specific (CSS), and overall survival (OS)] were stratified by BAP1 status. The prognostic role of BAP1 was assessed using Kaplan–Meier (KM) and Cox regression analysis. Significance was defined as p < 0.05.

Results

348 patients were included for analysis and 173 (49.7%) showed BAP1 loss. Median follow-up was 36.0 months. BAP1 loss was associated with papillary architecture and absence of tumor necrosis or CIS. On univariable analysis, BAP1 loss was associated with improved RFS (HR 0.60, p = 0.013) and CSS (HR 0.55, p = 0.007), although significance was lost on multivariable analysis (HR 0.71, p = 0.115 and HR 0.65, p = 0.071; respectively) after adjusting for other significant parameters. BAP1 expression was not significantly associated with OS.

Conclusions

BAP1 loss was associated with favorable pathologic features and better oncologic outcomes in univariate but not multivariate analysis in patients with high-grade UTUC. In contrast to renal cell carcinoma, loss of BAP1 expression appears to confer a better prognosis in high-grade UTUC. The role of the BAP1 pathway in UTUC pathogenesis remains to be further elucidated.

Keywords

BAP1 protein Human Biomarkers Carcinoma Transitional cell Prognosis Urinary tract 

Notes

Author contributions

Protocol/project development: AMA, NS, PK, VM, LMK. Data collection: AMA, NS, PK, CGW, JAK, AZW, JDR, MR, NRL, AH, MR, CB, KB, MEW, AIS, SFS, YL, AB, PK, VM, LMK. Data management: AMA, NS, VP, SLW, PK, VM, LMK. Data analysis: NS, VP, SLW, YF, VM, LMK. Manuscript writing: AMA, NS, LMK. Manuscript editing: AMA, CGW, JAK, AZW, JDR, MR, NRL, AH, MR, CB, KB, MEW, AIS, SFS, YL, AB, PK, VM, LMK. All authors approved the final manuscript.

Compliance with ethical standards

Conflict of interest

We declare that there are no potential competing interests in this research.

Ethical standards

This study was conducted according to the Declaration of Helsinki and institutional review board approval was obtained at each center participating in this research. An institutional IRB was granted through a local ethics committee at each location.

Supplementary material

345_2019_2678_MOESM1_ESM.pptx (5 mb)
Supplementary material 1 (PPTX 5170 kb) Examples of positive BAP1 expression (a and b) and loss of BAP1 (c and d)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Ahmet M. Aydin
    • 1
    • 2
  • Nirmish Singla
    • 1
  • Vandana Panwar
    • 3
  • Solomon L. Woldu
    • 1
  • Yuval Freifeld
    • 1
  • Christopher G. Wood
    • 4
  • Jose A. Karam
    • 4
  • Alon Z. Weizer
    • 5
  • Jay D. Raman
    • 6
  • Mesut Remzi
    • 7
  • Nathalie Rioux-Leclercq
    • 8
  • Andrea Haitel
    • 9
  • Marco Roscigno
    • 10
  • Christian Bolenz
    • 11
  • Karim Bensalah
    • 12
  • Mary E. Westerman
    • 1
    • 13
  • Arthur I. Sagalowsky
    • 1
  • Shahrokh F. Shariat
    • 7
  • Yair Lotan
    • 1
  • Aditya Bagrodia
    • 1
  • Payal Kapur
    • 3
  • Vitaly Margulis
    • 1
    Email author
  • Laura-Maria Krabbe
    • 1
    • 14
  1. 1.Department of UrologyUniversity of Texas Southwestern Medical CenterDallasUSA
  2. 2.Department of UrologyHacettepe UniversityAnkaraTurkey
  3. 3.Department of PathologyUniversity of Texas Southwestern Medical CenterDallasUSA
  4. 4.Department of UrologyMD Anderson Cancer CenterHoustonUSA
  5. 5.Department of UrologyUniversity of Michigan Cancer CenterAnn ArborUSA
  6. 6.Division of UrologyPenn State Milton S. Hershey Medical CenterHersheyUSA
  7. 7.Department of UrologyMedical University of ViennaViennaAustria
  8. 8.Department of PathologyCentre Hospitalier Universitaire de RennesRennesFrance
  9. 9.Department of PathologyMedical University ViennaViennaAustria
  10. 10.Department of UrologyOspedali Riuniti of BergamoBergamoItaly
  11. 11.Department of UrologyUniversity of UlmUlmGermany
  12. 12.Department of UrologyCentre Hospitalier Universitaire de RennesRennesFrance
  13. 13.Department of UrologyMayo ClinicRochesterUSA
  14. 14.Department of UrologyUniversity of Muenster Medical CenterMuensterGermany

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