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.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
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
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
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
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
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
Bartek J, Lukas J (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3(5):421–429
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
We would like to thank Stefanie Goetz for excellent technical support.
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 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).
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
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
- Non-muscle-invasive bladder cancer
- Smoking status