Skip to main content

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

Pathology & Oncology Research volume 26, pages 1625–1632 (2020)Cite this article

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.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424

    PubMed  PubMed Central  Google Scholar 

  2. Babjuk M, Böhle A, Burger M, Capoun O, Cohen D, Compérat EM, Hernández V, Kaasinen E, Palou J, Rouprêt M, van Rhijn BW, Shariat SF, Soukup V, Sylvester RJ, Zigeuner R (2017) EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol 71(3):447–461

    Article  Google Scholar 

  3. Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, Newling DW, Kurth K (2006) Predicting recurrence and progression in individual patients with stage ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 49:466–475 discussion 475–477

    Article  Google Scholar 

  4. Denzinger S, Fritsche HM, Otto W, Blana A, Wieland WF, Burger M (2008) Early versus deferred cystectomy for initial high-risk pT1G3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladdersparing approach? Eur Urol 53:146–152

    Article  Google Scholar 

  5. Heeke AL, Pishvaian MJ, Lynce F, Xiu J, Brody JR, Chen WJ, Baker TM, Marshall JL, Isaacs C (2018) Prevalence of homologous recombination-related gene mutations across multiple Cancer types. JCO Precis Oncol 2018:1–13. https://doi.org/10.1200/PO.17.00286. Epub 2018 Jul 23

    Article  Google Scholar 

  6. Bartek J, Lukas J (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3(5):421–429

    CAS  Article  Google Scholar 

  7. Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ, Mak TW (2000) DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science 287(5459):1824–1827

    CAS  Article  Google Scholar 

  8. Suchy J, Cybulski C, Wokołorczyk D, Oszurek O, Górski B, Debniak T, Jakubowska A, Gronwald J, Huzarski T, Byrski T, Dziuba I, Gogacz M, Wiśniowski R, Wandzel P, Banaszkiewicz Z, Kurzawski G, Kładny J, Narod SA, Lubiński J (2010) CHEK2 mutations and HNPCC-related colorectal cancer. Int J Cancer 126(12):3005–3009. https://doi.org/10.1002/ijc.25003

    CAS  Article  PubMed  Google Scholar 

  9. Havranek O, Spacek M, Hubacek P, Mocikova H, Markova J, Trneny M, Kleibl Z (2011) Alterations of CHEK2 forkhead-associated domain increase the risk of Hodgkin lymphoma. Neoplasma 58(5):392–395

    CAS  Article  Google Scholar 

  10. Havranek O, Kleiblova P, Hojny J, Lhota F, Soucek P, Trneny M, Kleibl Z (2015) Association of Germline CHEK2 gene variants with risk and prognosis of non-Hodgkin lymphoma. PLoS One 10(10):e0140819. https://doi.org/10.1371/journal.pone.0140819eCollection 2015

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Wang Y, Dai B, Ye D (2015) CHEK2 mutation and risk of prostate cancer: a systematic review and meta-analysis. Int J Clin Exp Med 8(9):15708–15715 eCollection 2015

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Złowocka E, Cybulski C, Górski B, Debniak T, Słojewski M, Wokołorczyk D, Serrano-Fernández P, Matyjasik J, van de Wetering T, Sikorski A, Scott RJ, Lubiński J (2008) Germline mutations in the CHEK2 kinase gene are associated with an increased risk of bladder cancer. Int J Cancer 122(3):583–586

    Article  Google Scholar 

  13. Lee HE, Han N, Kim MA, Lee HS, Yang HK, Lee BL, Kim WH (2014) DNA damage response-related proteins in gastric cancer: ATM, Chk2 and p53 expression and their prognostic value. Pathobiology 81(1):25–35. https://doi.org/10.1159/000351072 Epub 2013 Aug 21

    CAS  Article  PubMed  Google Scholar 

  14. Ow GS, Ivshina AV, Fuentes G, Kuznetsov VA (2014) Identification of two poorly prognosed ovarian carcinoma subtypes associated with CHEK2 germ-line mutation and non-CHEK2 somatic mutation gene signatures. Cell Cycle 13(14):2262–2280. https://doi.org/10.4161/cc.29271 Epub 2014 May 30

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Słojewski M, Złowocka E, Cybulski C, Górski B, Debniak T, Wokołorczyk D, Matyjasik J, Sikorski A, Lubiński J (2008) CHEK2 germline mutations correlate with recurrence rate in patients with superficial bladder cancer. Ann Acad Med Stetin 54(3):115–121

    PubMed  Google Scholar 

  16. Shahin O, Thalmann GN, Rentsch C, Mazzucchelli L, Studer UE (2003) A retrospective analysis of 153 patients treated with or without intravesical bacillus Calmette-Guerin for primary stage T1 grade 3 bladder cancer: recurrence, progression and survival. J Urol 169(1):96–100

    CAS  Article  Google Scholar 

  17. Aziz A, May M, Burger M, Palisaar RJ, Trinh QD, Fritsche HM, Rink M, Chun F, Martini T, Bolenz C, Mayr R, Pycha A, Nuhn P, Stief C, Novotny V, Wirth M, Seitz C, Noldus J, Gilfrich C, Shariat SF, Brookman-May S, Bastian PJ, Denzinger S, Gierth M, Roghmann F (2014) PROMETRICS 2011 research group. Prediction of 90-day mortality after radical cystectomy for bladder cancer in a prospective European multicenter cohort. Eur Urol 66(1):156–163

    Article  Google Scholar 

  18. Ge Y, Wang Y, Shao W, Jin J, Du M, Ma G, Chu H, Wang M, Zhang Z (2016) Rare variants in BRCA2 and CHEK2 are associated with the risk of urinary tract cancers. Sci Rep 6:33542. https://doi.org/10.1038/srep33542

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Muranen TA, Blomqvist C, Dörk T, Jakubowska A, Heikkilä P, Fagerholm R, Greco D, Aittomäki K, Bojesen SE, Shah M, Dunning AM, Rhenius V, Hall P, Czene K, Brand JS, Darabi H, Chang-Claude J, Rudolph A, Nordestgaard BG, Couch FJ, Hart SN, Figueroa J, García-Closas M, Fasching PA, Beckmann MW, Li J, Liu J, Andrulis IL, Winqvist R, Pylkäs K, Mannermaa A, Kataja V, Lindblom A, Margolin S, Lubinski J, Dubrowinskaja N, Bolla MK, Dennis J, Michailidou K, Wang Q, Easton DF, Pharoah PD, Schmidt MK, Nevanlinna H (2016) Patient survival and tumor characteristics associated with CHEK2:p.I157T - findings from the Breast Cancer Association Consortium. Breast Cancer Res 18(1):98

    Article  Google Scholar 

  20. Kilpivaara O, Bartkova J, Eerola H, Syrjäkoski K, Vahteristo P, Lukas J, Blomqvist C, Holli K, Heikkilä P, Sauter G, Kallioniemi OP, Bartek J, Nevanlinna H (2005) Correlation of CHEK2 protein expression and c.1100delC mutation status with tumor characteristics among unselected breast cancer patients. Int J Cancer 113(4):575–580

    CAS  Article  Google Scholar 

  21. de Bock GH, Schutte M, Krol-Warmerdam EM, Seynaeve C, Blom J, Brekelmans CT, Meijers-Heijboer H, van Asperen CJ, Cornelisse CJ, Devilee P, Tollenaar RA, Klijn JG (2004) Tumour characteristics and prognosis of breast cancer patients carrying the germline CHEK2*1100delC variant. J Med Genet 41(10):731–735

    Article  Google Scholar 

  22. Ribeiro-Silva A, Moutinho MA, Moura HB, Vale FR, Zucoloto S (2006) Expression of checkpoint kinase 2 in breast carcinomas: correlation with key regulators of tumor cell proliferation, angiogenesis, and survival. Histol Histopathol 21(4):373–382. https://doi.org/10.14670/HH-21.373

    CAS  Article  PubMed  Google Scholar 

  23. Kriege M, Hollestelle A, Jager A, Huijts PE, Berns EM, Sieuwerts AM, Meijer-van Gelder ME, Collée JM, Devilee P, Hooning MJ, Martens JW, Seynaeve C (2014) Survival and contralateral breast cancer in CHEK2 1100delC breast cancer patients: impact of adjuvant chemotherapy. Br J Cancer 111(5):1004–1013. https://doi.org/10.1038/bjc.2014.306 Epub 2014 Jun 10

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Teodorczyk U, Cybulski C, Wokołorczyk D, Jakubowska A, Starzyńska T, Lawniczak M, Domagała P, Ferenc K, Marlicz K, Banaszkiewicz Z, Wiśniowski R, Narod SA, Lubiński J (2013) The risk of gastric cancer in carriers of CHEK2 mutations. Familial Cancer 12(3):473–478. https://doi.org/10.1007/s10689-012-9599-2

    CAS  Article  PubMed  Google Scholar 

  25. Ghelli Luserna Di Rorà A, Iacobucci I, Imbrogno E, Papayannidis C, Derenzini E, Ferrari A, Guadagnuolo V, Robustelli V, Parisi S, Sartor C, Abbenante MC, Paolini S, Martinelli G (2016) Prexasertib, a Chk1/Chk2 inhibitor, increases the effectiveness of conventional therapy in B−/T- cell progenitor acute lymphoblastic leukemia. Oncotarget 7(33):53377–53391. https://doi.org/10.18632/oncotarget.10535

    Article  PubMed  Google Scholar 

  26. Zeng L, Beggs RR, Cooper TS, Weaver AN, Yang ES (2017) Combining Chk1/2 inhibition with Cetuximab and radiation enhances In Vitro and In VivoCytotoxicity in head and neck squamous cell carcinoma. Mol Cancer Ther 16(4):591–600. https://doi.org/10.1158/1535-7163.MCT-16-0352 Epub 2017 Jan 30

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Isono M, Hoffmann MJ, Pinkerneil M, Sato A, Michaelis M, Cinatl J Jr, Niegisch G, Schulz WA (2017) Checkpoint kinase inhibitor AZD7762 strongly sensitises urothelial carcinoma cells to gemcitabine. J Exp Clin Cancer Res 36(1):1. https://doi.org/10.1186/s13046-016-0473-1

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Zhao H, Albino AP, Jorgensen E, Traganos F, Darzynkiewicz Z (2009) DNA damage response induced by tobacco smoke in normal human bronchial epithelial and A549 pulmonary adenocarcinoma cells assessed by laser scanning cytometry. Cytometry A 75(10):840–847. https://doi.org/10.1002/cyto.a.20778

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Breyer J, Denzinger S, Hartmann A, Otto W (2016) Downregulation of checkpoint protein kinase 2 in the Urothelium of healthy male tobacco smokers. Urol Int 97(4):480–481 Epub 2016 Jun 2

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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

Author information

Affiliations

  1. Department of Urology, Caritas St. Josef Medical Center, University of Regensburg, Landshuter Str. 65, 93053, Regensburg, Germany

    Philipp J. Spachmann, Vanessa Azzolina, Stefan Denzinger, Maximilian Burger, Wolfgang Otto & Johannes Breyer

  2. Institute of Pathology, University of Regensburg, Regensburg, Germany

    Florian Weber & Matthias Evert

  3. Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    Markus Eckstein

Authors
  1. Philipp J. Spachmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vanessa Azzolina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Florian Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Matthias Evert
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Markus Eckstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stefan Denzinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maximilian Burger
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wolfgang Otto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Johannes Breyer
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Ethics declarations

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).

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-019-00745-7

Keywords

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