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Loss of CHEK2 Predicts Progression in Stage pT1 Non-Muscle-Invasive Bladder Cancer (NMIBC)

  • Philipp J. SpachmannEmail author
  • Vanessa Azzolina
  • Florian Weber
  • Matthias Evert
  • Markus Eckstein
  • Stefan Denzinger
  • Maximilian Burger
  • Wolfgang Otto
  • Johannes Breyer
Original Article
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Abstract

Downregulation of checkpoint protein kinase 2 (CHEK2), which is involved in DNA repair, is associated with poorer outcome in various tumors. Little is known about the role of CHEK2 in urothelial carcinoma of the bladder (UCB). In the present study, we investigated the prognostic impact of CHEK2 protein expression in stage pT1 UCB. This retrospective, single-center analysis was carried out in a cohort of patients initially diagnosed with a pT1 UCB between 2007 and 2015. Immunohistochemical (IHC) staining of CHEK2 was performed. CHEK2 expression was correlated with recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS) using Kaplan-Meier analysis and multivariable Cox regression analysis. The analysis included 126 patients (86% male, median age 71 years). Loss of immunohistochemical protein expression of CHEK2 (<10%) was associated with significantly worse PFS (p = 0.041). Likewise, CHEK2 loss identified a subgroup of patients with worse PFS in the high-risk groups with concomitant CIS (p = 0.044), multifocal tumors (p < 0.001) and tumor grading G3 according to WHO1973 (p = 0.009). Multivariable Cox regression analysis revealed both loss of CHEK2 expression (HR: 4.18, 95%-CI: 1.35–12.93; p = 0.013) and multifocal tumors (HR: 4.53, 95%-CI:1.29–15.92; p = 0.018) as the only predictive factors for progression. Loss of IHC expression of CHEK2 in pT1 UCB is an independent predictor for progression to muscle-invasive disease and is also associated with worse PFS. This could help to identify high-risk patients who would benefit from early cystectomy.

Keywords

Non-muscle-invasive bladder cancer NMIBC CHEK2 Smoking status Progression 

Notes

Acknowledgements

We would like to thank Stefanie Goetz for excellent technical support.

Author’s Contribution

Protocol/project development: Denzinger, Burger, Otto, Breyer.

Data collection or management: Azzolina, Weber, Evert, Eckstein, Breyer.

Data analysis: Spachmann, Otto, Breyer.

Manuscript writing/editing: Spachmann, Breyer.

Compliance with Ethical Standards

Conflict of Interest

No potential conflicts of interest must be reported.

Research Involving Human Participants and/or Animals

Research did not involve human participants or animals.

Informed Consent

Informed consent was obtained from all individual participants included in the study. All the findings, data acquisition and processing in this study comply with the ethical standards laid down in the latest declaration of Helsinki. The study was approved by the local ethics committee of the University of Regensburg (Nr. 16–321-101).

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Copyright information

© Arányi Lajos Foundation 2019

Authors and Affiliations

  • Philipp J. Spachmann
    • 1
    Email author
  • Vanessa Azzolina
    • 1
  • Florian Weber
    • 2
  • Matthias Evert
    • 2
  • Markus Eckstein
    • 3
  • Stefan Denzinger
    • 1
  • Maximilian Burger
    • 1
  • Wolfgang Otto
    • 1
  • Johannes Breyer
    • 1
  1. 1.Department of Urology, Caritas St. Josef Medical CenterUniversity of RegensburgRegensburgGermany
  2. 2.Institute of PathologyUniversity of RegensburgRegensburgGermany
  3. 3.Institute of Pathology, University Hospital ErlangenFriedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany

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