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

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.

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Acknowledgements

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

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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.

Corresponding author

Correspondence to Philipp J. Spachmann.

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Research did not involve human participants or animals.

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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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Spachmann, P.J., Azzolina, V., Weber, F. et al. Loss of CHEK2 Predicts Progression in Stage pT1 Non-Muscle-Invasive Bladder Cancer (NMIBC). Pathol. Oncol. Res. 26, 1625–1632 (2020). https://doi.org/10.1007/s12253-019-00745-7

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Keywords

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