nach oben

Journal of Cancer Research and Clinical Oncology

Erschienen in:

01.02.2016 | Original Article – Cancer Research

Diagnostic and prognostic value of bladder cancer-related transcript markers in urine

verfasst von: Juliane Schmidt, Catharina Propping, Woei-Yun Siow, Andrea Lohse-Fischer, Marieta Toma, Anka Baldauf-Twelker, Oliver W. Hakenberg, Manfred P. Wirth, Susanne Fuessel

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 2/2016

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Since cytology as the current “gold standard” for noninvasive detection of bladder cancer (BCa) is characterized by a relatively low sensitivity, urinary transcript levels of survivin (SVV), Ki-67 and cytokeratin 20 (CK20) were evaluated as alternative or complementary biomarkers. Furthermore, their prognostic value was investigated.

Methods

Voided urine samples from 105 BCa patients and 156 controls were included. Total RNA was isolated from urine pellets and reverse-transcribed into cDNA. Expression levels of SVV, Ki-67 and CK20 were determined by quantitative PCR and normalized to the housekeeping gene TBP. Diagnostic performance of transcript markers and cytology was assessed by receiver operating characteristic (ROC) curve analyses. The prognostic value of the transcript markers was calculated by Cox proportional hazards models.

Results

ROC analyses resulted in AUC values between 0.71 (Ki-67) and 0.86 (CK20), indicating an appropriate diagnostic power. Using specifically defined cutoff values, the expression levels of the assessed biomarkers were significantly higher in urine specimens from BCa patients compared to control group (Mann–Whitney U test p < 0.001). Specificity ranged from 75 % (SVV) to 84 % (CK20) and sensitivity from 56 % (Ki-67) to 87 % (CK20). In combination with cytology, the sensitivity increased up to 97 % (CK20). With regard to prognostic power, only SVV showed a significant, but not independent impact on the risk of recurrence (p = 0.008).

Conclusions

Quantitative assessment of tumor-related transcript markers, particularly of CK20, may serve as a noninvasive method to identify patients with BCa. Moreover, SVV appears to be useful as a marker for a high risk of recurrence.

Nur mit Berechtigung zugänglich

Akobeng AK (2007) Understanding diagnostic tests 3: receiver operating characteristic curves. Acta Paediatr. doi:10.1111/j.1651-2227.2006.00178.x

Al-Maghrebi M, Kehinde EO, Kapila K, Anim JT (2012) Urinary survivin mRNA expression and urinary nuclear matrix protein 22 BladderChek(R) and urine cytology in the detection of transitional cell carcinoma of the bladder. Med Princ Pract. doi:10.1159/000334811 PubMed

Babjuk M, Burger M, Zigeuner R, Shariat SF, van Rhijn BW, Comperat E, Sylvester RJ, Kaasinen E, Bohle A, Palou Redorta J, Roupret M (2013) EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol. doi:10.1016/j.eururo.2013.06.003

Bassily NH, Vallorosi CJ, Akdas G, Montie JE, Rubin MA (2000) Coordinate expression of cytokeratins 7 and 20 in prostate adenocarcinoma and bladder urothelial carcinoma. Am J Clin Pathol. doi:10.1309/G1RA-EU9X-X6VV-3W79 PubMed

Christoph F, Weikert S, Wolff I, Schostak M, Tabiti K, Muller M, Miller K, Schrader M (2007) Urinary cytokeratin 20 mRNA expression has the potential to predict recurrence in superficial transitional cell carcinoma of the bladder. Cancer Lett. doi:10.1016/j.canlet.2005.12.038

Duffy MJ, O’Donovan N, Brennan DJ, Gallagher WM, Ryan BM (2007) Survivin: a promising tumor biomarker. Cancer Lett. doi:10.1016/j.canlet.2006.12.020 PubMed

Eissa S, Kassim S, El-Ahmady O (2003) Detection of bladder tumours: role of cytology, morphology-based assays, biochemical and molecular markers. Curr Opin Obstet Gynecol. doi:10.1097/01.gco.0000094701.87578.e0 PubMed

Eissa S, Kenawy G, Swellam M, El-Fadle AA, Abd El-Aal AA, El-Ahmady O (2004) Comparison of cytokeratin 20 RNA and angiogenin in voided urine samples as diagnostic tools for bladder carcinoma. Clin Biochem. doi:10.1016/j.clinbiochem.2004.05.027 PubMed

Eissa S, Kassim SK, Labib RA, El-Khouly IM, Ghaffer TM, Sadek M, Razek OA, El-Ahmady O (2005) Detection of bladder carcinoma by combined testing of urine for hyaluronidase and cytokeratin 20 RNAs. Cancer. doi:10.1002/cncr.20902 PubMed

Eissa S, Zohny SF, Swellam M, Mahmoud MH, El-Zayat TM, Salem AM (2008) Comparison of CD44 and cytokeratin 20 mRNA in voided urine samples as diagnostic tools for bladder cancer. Clin Biochem. doi:10.1016/j.clinbiochem.2008.08.085 PubMed

Eissa S, Swellam M, Shehata H, El-Khouly IM, El-Zayat T, El-Ahmady O (2010) Expression of HYAL1 and survivin RNA as diagnostic molecular markers for bladder cancer. J Urol. doi:10.1016/j.juro.2009.10.024 PubMed

Eissa S, Swellam M, Amin A, Balbaa ME, Yacout GA, El-Zayat TM (2011) The clinical relevance of urine-based markers for diagnosis of bladder cancer. Med Oncol. doi:10.1007/s12032-010-9422-6

Eissa S, Badr S, Elhamid SA, Helmy AS, Nour M, Esmat M (2013) The value of combined use of survivin mRNA and matrix metalloproteinase 2 and 9 for bladder cancer detection in voided urine. Dis Markers. doi:10.3233/dma-2012-0923 PubMedPubMedCentral

Gerdes J, Schwab U, Lemke H, Stein H (1983) Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Cancer 31:13–20PubMedCrossRef

Giannopoulos A, Manousakas T, Gounari A, Constantinides C, Choremi-Papadopoulou H, Dimopoulos C (2001) Comparative evaluation of the diagnostic performance of the BTA stat test, NMP22 and urinary bladder cancer antigen for primary and recurrent bladder tumors. J Urol 166:470–475PubMedCrossRef

Guo B, Luo C, Xun C, Xie J, Wu X, Pu J (2009) Quantitative detection of cytokeratin 20 mRNA in urine samples as diagnostic tools for bladder cancer by real-time PCR. Exp Oncol 31:43–47PubMed

Horstmann M, Bontrup H, Hennenlotter J, Taeger D, Weber A, Pesch B, Feil G, Patschan O, Johnen G, Stenzl A, Bruning T (2010) Clinical experience with survivin as a biomarker for urothelial bladder cancer. World J Urol. doi:10.1007/s00345-010-0538-2

Hou JQ, He J, Wen DG, Chen ZX, Zeng J (2006) Survivin mRNA expression in urine as a biomarker for patients with transitional cell carcinoma of bladder. Chin Med J (Engl) 119:1118–1120

Inoue T, Nakanishi H, Inada K, Hioki T, Tatematsu M, Sugimura Y (2001) Real time reverse transcriptase polymerase chain reaction of urinary cytokeratin 20 detects transitional cell carcinoma cells. J Urol 166:2134–2141PubMedCrossRef

Johnen G, Gawrych K, Bontrup H, Pesch B, Taeger D, Banek S, Kluckert M, Wellhausser H, Eberle F, Nasterlack M, Leng G, Stenzl A, Bruning T (2012) Performance of survivin mRNA as a biomarker for bladder cancer in the prospective study UroScreen. PLoS One. doi:10.1371/journal.pone.0035363

Kamat AM, Hegarty PK, Gee JR, Clark PE, Svatek RS, Hegarty N, Shariat SF, Xylinas E, Schmitz-Drager BJ, Lotan Y, Jenkins LC, Droller M, van Rhijn BW, Karakiewicz PI (2013) ICUD-EAU International Consultation on Bladder Cancer 2012: screening, diagnosis, and molecular markers. Eur Urol. doi:10.1016/j.eururo.2012.09.057

Karam JA, Lotan Y, Ashfaq R, Sagalowsky AI, Shariat SF (2007) Survivin expression in patients with non-muscle-invasive urothelial cell carcinoma of the bladder. Urology. doi:10.1016/j.urology.2007.05.009 PubMed

Limas C, Frizelle SP (1994) Proliferative activity in benign and neoplastic prostatic epithelium. J Pathol. doi:10.1002/path.1711740309 PubMed

Lokeshwar VB, Soloway MS (2001) Current bladder tumor tests: does their projected utility fulfill clinical necessity? J Urol 165:1067–1077PubMedCrossRef

Lokeshwar VB, Habuchi T, Grossman HB, Murphy WM, Hautmann SH, Hemstreet GP, Bono AV, Getzenberg RH, Goebell P, Schmitz-Drager BJ, Schalken JA, Fradet Y, Marberger M, Messing E, Droller MJ (2005) Bladder tumor markers beyond cytology: International Consensus Panel on bladder tumor markers. Urology. doi:10.1016/j.urology.2005.08.064

Margulis V, Shariat SF, Ashfaq R, Sagalowsky AI, Lotan Y (2006) Ki-67 is an independent predictor of bladder cancer outcome in patients treated with radical cystectomy for organ-confined disease. Clin Cancer Res. doi:10.1158/1078-0432.ccr-06-1472 PubMed

Menke TB, Boettcher K, Kruger S, Kausch I, Boehle A, Sczakiel G, Warnecke JM (2004) Ki-67 protein concentrations in urothelial bladder carcinomas are related to Ki-67-specific RNA concentrations in urine. Clin Chem. doi:10.1373/clinchem.2003.030049 PubMed

Moll R, Lowe A, Laufer J, Franke WW (1992) Cytokeratin 20 in human carcinomas. A new histodiagnostic marker detected by monoclonal antibodies. Am J Pathol 140:427–447PubMedPubMedCentral

Moll R, Divo M, Langbein L (2008) The human keratins: biology and pathology. Histochem Cell Biol. doi:10.1007/s00418-008-0435-6 PubMedPubMedCentral

Muschol-Steinmetz C, Friemel A, Kreis NN, Reinhard J, Yuan J, Louwen F (2013) Function of survivin in trophoblastic cells of the placenta. PLoS One. doi:10.1371/journal.pone.0073337 PubMedPubMedCentral

Pu XY, Wang ZP, Chen YR, Wang XH, Wu YL, Wang HP (2008) The value of combined use of survivin, cytokeratin 20 and mucin 7 mRNA for bladder cancer detection in voided urine. J Cancer Res Clin Oncol. doi:10.1007/s00432-007-0331-9

Ramos D, Navarro S, Villamon R, Gil-Salom M, Llombart-Bosch A (2003) Cytokeratin expression patterns in low-grade papillary urothelial neoplasms of the urinary bladder. Cancer. doi:10.1002/cncr.11265 PubMed

Retz M, Lehmann J, Amann E, Wullich B, Roder C, Stockle M (2003) Mucin 7 and cytokeratin 20 as new diagnostic urinary markers for bladder tumor. J Urol. doi:10.1097/01.ju.0000039900.41604.a2 PubMed

Rotem D, Cassel A, Lindenfeld N, Mecz Y, Sova Y, Resnick M, Stein A (2000) Urinary cytokeratin 20 as a marker for transitional cell carcinoma. Eur Urol. doi:10.1159/000020199 PubMed

Schultz IJ, Kiemeney LA, Karthaus HF, Witjes JA, Willems JL, Swinkels DW, Gunnewiek JM, de Kok JB (2004) Survivin mRNA copy number in bladder washings predicts tumor recurrence in patients with superficial urothelial cell carcinomas. Clin Chem. doi:10.1373/clinchem.2004.032003 PubMed

Schultz IJ, Kiemeney LA, Willems JL, Swinkels DW, Witjes JA, de Kok JB (2006) Survivin and MKI67 mRNA expression in bladder washings of patients with superficial urothelial cell carcinoma correlate with tumor stage and grade but do not predict tumor recurrence. Clin Chem. doi:10.1373/clinchem.2006.071480 PubMed

Shariat SF, Ashfaq R, Roehrborn CG, Slawin KM, Lotan Y (2005) Expression of survivin and apoptotic biomarkers in benign prostatic hyperplasia. J Urol. doi:10.1097/01.ju.0000176459.79180.d1

Siracusano S, Niccolini B, Knez R, Tiberio A, Benedetti E, Bonin S, Ciciliato S, Pappagallo GL, Belgrano E, Stanta G (2005) The simultaneous use of telomerase, cytokeratin 20 and CD4 for bladder cancer detection in urine. Eur Urol. doi:10.1016/j.eururo.2004.10.007

Spaulding B, Pan D, Ghadersohi A, Nielsen G, Jensen S, Gellert F, Ling X, Zhang M, Black A, Li F (2006) Characterization of the 12C4 survivin monoclonal antibody and insight into the expression of survivin in human adult tissues. Histopathology. doi:10.1111/j.1365-2559.2006.02556.x PubMedPubMedCentral

Velculescu VE, Madden SL, Zhang L, Lash AE, Yu J, Rago C, Lal A, Wang CJ, Beaudry GA, Ciriello KM, Cook BP, Dufault MR, Ferguson AT, Gao Y, He TC, Hermeking H, Hiraldo SK, Hwang PM, Lopez MA, Luderer HF, Mathews B, Petroziello JM, Polyak K, Zawel L, Kinzler KW et al (1999) Analysis of human transcriptomes. Nat Genet. doi:10.1038/70487 PubMed

Weikert S, Christoph F, Schrader M, Krause H, Miller K, Muller M (2005) Quantitative analysis of survivin mRNA expression in urine and tumor tissue of bladder cancer patients and its potential relevance for disease detection and prognosis. Int J Cancer. doi:10.1002/ijc.21000

Youssef RF, Lotan Y (2011) Predictors of outcome of non-muscle-invasive and muscle-invasive bladder cancer. Sci World J. doi:10.1100/tsw.2011.28

Zaffaroni N, Pennati M, Daidone MG (2005) Survivin as a target for new anticancer interventions. J Cell Mol Med 9:360–372PubMedCrossRef

Titel: Diagnostic and prognostic value of bladder cancer-related transcript markers in urine
verfasst von: Juliane Schmidt
Catharina Propping
Woei-Yun Siow
Andrea Lohse-Fischer
Marieta Toma
Anka Baldauf-Twelker
Oliver W. Hakenberg
Manfred P. Wirth
Susanne Fuessel
Publikationsdatum: 01.02.2016
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 2/2016
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-015-2037-8

Springer Medizin

Diagnostic and prognostic value of bladder cancer-related transcript markers in urine