Abstract
Bladder cancer (BC) is classified as non-muscle-invasive BC (NMIBC) or muscle-invasive BC (MIBC). Because the recurrence and mortality rates of BC are high, suitable biomarkers for early detection, evaluation of prognosis, and surveillance of drug responses are needed. Urinary markers simplify surveillance schedules and improve early detection of tumors, especially in NMIBC. Various markers have been identified at DNA, RNA, and protein levels with different sensitivities and specificities. Several biomarkers show a higher sensitivity than urinary cytology, but they are not accurate enough to replace it. In terms of prediction of clinical outcome and treatment response of BC, conventional clinical and pathological parameters are widely used, but the predictive ability of these parameters is limited; therefore, molecular biomarkers in this field are strongly desired. Molecular profiling using fluid and tissue is becoming more feasible with recent developments in next-generation sequencing technologies. Currently, these profiling methods are beginning to be used for early detection, prediction of prognosis, and drug sensitivity. Furthermore, several groups used transcriptome profiling to classify MIBC into various distinct subtypes, showing distinct clinical behaviors and responses to chemotherapy and immune checkpoint inhibitors. The aim of this review is to provide a summary of the most relevant biomarkers that have been investigated as diagnostic and prognostic indicators of BC.
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Ferlay J, Soerjomataram I, Dikshit R et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386. doi:10.1002/ijc.29210
Yafi FA, Brimo F, Steinberg J et al (2015) Prospective analysis of sensitivity and specificity of urinary cytology and other urinary biomarkers for bladder cancer. Urol Oncol 33(2):66.e25–e31. doi:10.1016/j.urolonc.2014.06.008
Rosser CJ, Chang M, Dai Y et al (2014) Urinary protein biomarker panel for the detection of recurrent bladder cancer. Cancer Epidemiol Biomarkers Prev 23(7):1340–1345. doi:10.1158/1055-9965.EPI-14-0035
Lotan Y, Roehrborn CG (2003) Sensitivity and specificity of commonly available bladder tumor markers versus cytology: results of a comprehensive literature review and meta-analyses. Urology 61(1):109–118
Grossman HB, Messing E, Soloway M et al (2005) Detection of bladder cancer using a point-of-care proteomic assay. JAMA 293(7):810–816
Shariat SF, Savage C, Chromecki TF et al (2011) Assessing the clinical benefit of nuclear matrix protein 22 in the surveillance of patients with nonmuscle-invasive bladder cancer and negative cytology: a decision-curve analysis. Cancer 117(13):2892–2897. doi:10.1002/cncr.25903
Ho CC, Tan WP, Pathmanathan R et al (2013) Fluorescence-in situ-hybridization in the surveillance of urothelial cancers: can use of cystoscopy or ureteroscopy be deferred? Asian Pac J Cancer Prev 14(7):4057–4059
Black PC, Brown GA, Dinney CP (2006) Molecular markers of urothelial cancer and their use in the monitoring of superficial urothelial cancer. J Clin Oncol 24(35):5528–5535
Yoder BJ, Skacel M, Hedgepeth R et al (2007) Reflex UroVysion testing of bladder cancer surveillance patients with equivocal or negative urine cytology: a prospective study with focus on the natural history of anticipatory positive findings. Am J Clin Pathol 127(2):295–301
Hajdinjak T (2008) UroVysion FISH test for detecting urothelial cancers: meta-analysis of diagnostic accuracy and comparison with urinary cytology testing. Urol Oncol 26(6):646–651. doi:10.1016/j.urolonc.2007.06.002
Lokeshwar VB, Habuchi T, Grossman HB et al (2005) Bladder tumor markers beyond cytology: International Consensus Panel on bladder tumor markers. Urology 66:35–63
Whitson J, Berry A, Carroll P et al (2009) A multicolour fluorescence in situ hybridization test predicts recurrence in patients with high-risk superficial bladder tumours undergoing intravesical therapy. BJU Int 104(3):336–339. doi:10.1111/j.1464-410X.2009.08375.x
Savic S, Zlobec I, Thalmann GN et al (2009) The prognostic value of cytology and fluorescence in situ hybridization in the follow-up of nonmuscle-invasive bladder cancer after intravesical Bacillus Calmette-Guerin therapy. Int J Cancer 124(12):2899–2904. doi:10.1002/ijc.24258
Griffiths-Jones S, Grocock RJ, van Dongen S et al (2006) microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 34:D140–D144
Yoshino H, Seki N, Itesako T et al (2013) Aberrant expression of microRNAs in bladder cancer. Nat Rev Urol 10(7):396–404. doi:10.1038/nrurol.2013.113
Cheng Y, Deng X, Yang X et al (2015) Urine microRNAs as biomarkers for bladder cancer: a diagnostic meta-analysis. Onco Targets Therapy 8:2089–2096. doi:10.2147/OTT.S86908
Chen L, Cui Z, Liu Y et al (2015) MicroRNAs as biomarkers for the diagnostics of bladder cancer: a meta-analysis. Clin Lab 61(8):1101–1108
Clark SJ, Melki J (2002) DNA methylation and gene silencing in cancer: which is the guilty party? Oncogene 21(35):5380–5387
Dhawan D, Hamdy FC, Rehman I et al (2006) Evidence for the early onset of aberrant promoter methylation in urothelial carcinoma. J Pathol 209(3):336–343
Kandimalla R, van Tilborg AA, Zwarthoff EC (2013) DNA methylation-based biomarkers in bladder cancer. Nat Rev Urol 10(6):327–335. doi:10.1038/nrurol.2013.89
Phe V, Cussenot O, Roupret M (2009) Interest of methylated genes as biomarkers in urothelial cell carcinomas of the urinary tract. BJU Int 104(7):896–901. doi:10.1111/j.1464-410X.2009.08696.x
Yu J, Zhu T, Wang Z et al (2007) A novel set of DNA methylation markers in urine sediments for sensitive/specific detection of bladder cancer. Clin Cancer Res 13(24):7296–7304
Vinci S, Giannarini G, Selli C et al (2011) Quantitative methylation analysis of BCL2, hTERT, and DAPK promoters in urine sediment for the detection of non-muscle-invasive urothelial carcinoma of the bladder: a prospective, two-center validation study. Urol Oncol 29(2):150–156. doi:10.1016/j.urolonc.2009.01.003
Reinert T (2012) Methylation markers for urine-based detection of bladder cancer: the next generation of urinary markers for diagnosis and surveillance of bladder cancer. Adv Urol 2012:503271. doi:10.1155/2012/503271
Scher MB, Elbaum MB, Mogilevkin Y et al (2012) Detecting DNA methylation of the BCL2, CDKN2A and NID2 genes in urine using a nested methylation specific polymerase chain reaction assay to predict bladder cancer. J Urol 188(6):2101–2107. doi:10.1016/j.juro.2012.08.015
Costa VL, Henrique R, Danielsen SA et al (2011) TCF21 and PCDH17 methylation: an innovative panel of biomarkers for a simultaneous detection of urological cancers. Epigenetics 6(9):1120–1130. doi:10.4161/epi.6.9.16376
Ward DG, Baxter L, Gordon NS et al (2016) Multiplex PCR and next generation sequencing for the non-invasive detection of bladder cancer. PLoS One 11(2):e0149756. doi:10.1371/journal.pone.0149756
Hernández S, López-Knowles E, Lloreta J et al (2006) Prospective study of FGFR3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas. J Clin Oncol 24(22):3664–3671. doi:10.1200/JCO.2005.05.1771
Burger M, van der Aa MN, van Oers JM et al (2008) Prediction of progression of non-muscle-invasive bladder cancer by WHO 1973 and 2004 grading and by FGFR3 mutation status: a prospective study. Eur Urol 54(4):835–843. doi:10.1016/j.eururo.2007.12.026
van Oers JM, Wild PJ, Burger M et al (2007) FGFR3 mutations and a normal CK20 staining pattern define low-grade noninvasive urothelial bladder tumours. Eur Urol 52(3):760–768. doi:10.1016/j.eururo.2007.01.009
Dueñas M, Martínez-Fernández M, García-Escudero R et al (2015) PIK3CA gene alterations in bladder cancer are frequent and associate with reduced recurrence in non-muscle invasive tumors. Mol Carcinog 54(7):566–576. doi:10.1002/mc.22125
Knowles MA, Hurst CD (2015) Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer 15(1):25–41. doi:10.1038/nrc3817
Rebouissou S, Hérault A, Letouzé E et al (2012) CDKN2A homozygous deletion is associated with muscle invasion in FGFR3-mutated urothelial bladder carcinoma. J Pathol 227(3):315–324. doi:10.1002/path.4017
Kim PH, Cha EK, Sfakianos JP et al (2015) Genomic predictors of survival in patients with high-grade urothelial carcinoma of the bladder. Eur Urol 67(2):198–201. doi:10.1016/j.eururo.2014.06.050
Iyer G, Hanrahan AJ, Milowsky MI et al (2012) Genome sequencing identifies a basis for everolimus sensitivity. Science 338(6104):221. doi:10.1126/science.1226344
Singh D, Chan JM, Zoppoli P et al (2012) Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 337(6099):1231–1235. doi:10.1126/science.1220834
Wu YM, Su F, Kalyana-Sundaram S et al (2013) Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov 3(6):636–647. doi:10.1158/2159-8290.CD-13-0050
Majewski IJ, Mittempergher L, Davidson NM et al (2013) Identification of recurrent FGFR3 fusion genes in lung cancer through kinome-centred RNA sequencing. J Pathol 230(3):270–276. doi:10.1002/path.4209
Williams SV, Hurst CD, Knowles MA (2013) Oncogenic FGFR3 gene fusions in bladder cancer. Hum Mol Genet 22(4):795–803. doi:10.1093/hmg/dds486
Di Stefano AL, Fucci A, Frattini V et al (2015) Characterization, and inhibition of FGFR-TACC fusions in IDH wild-type glioma. Clin Cancer Res 21(14):3307–3317. doi:10.1158/1078-0432.CCR-14-2199
Carneiro BA, Elvin JA, Kamath SD et al (2015) FGFR3-TACC3: a novel gene fusion in cervical cancer. Gynecol Oncol Rep 13:53–56. doi:10.1016/j.gore.2015.06.005
Kurobe M, Kojima T, Nishimura K et al (2016) Development of RNA-FISH assay for detection of oncogenic FGFR3-TACC3 fusion genes in FFPE samples. PLoS One (in press)
Redelman-Sidi G, Glickman MS, Bochner BH (2014) The mechanism of action of BCG therapy for bladder cancer–a current perspective. Nat Rev Urol 11(3):153–162. doi:10.1038/nrurol.2014.15
Kawai K, Miyazaki J, Joraku A (2013) Bacillus Calmette-Guerin (BCG) immunotherapy for bladder cancer: current understanding and perspectives on engineered BCG vaccine. Cancer Sci 104(1):22–27. doi:10.1111/cas.12075
Saint F, Patard JJ, Maille P et al (2002) Prognostic value of a T helper 1 urinary cytokine response after intravesical bacillus Calmette-Guerin treatment for superficial bladder cancer. J Urol 167(1):364–367
Watanabe E, Matsuyama H, Matsuda K et al (2003) Urinary interleukin-2 may predict clinical outcome of intravesical bacillus Calmette-Guérin immunotherapy for carcinoma in situ of the bladder. Cancer Immunol Immunother 52(8):481–486. doi:10.1007/s00262-003-0384-9
Kumar A, Dubey D, Bansal P et al (2002) Urinary interleukin-8 predicts the response of standard and low dose intravesical bacillus Calmette-Guerin (modified Danish 1331 strain) for superficial bladder cancer. J Urol 68(5):2232–2235. doi:10.1097/01.ju.0000032140.56365.52
Thalmann GN, Sermier A, Rentsch C et al (2000) Urinary Interleukin-8 and 18 predict the response of superficial bladder cancer to intravesical therapy with bacillus Calmette-Guerin. J Urol 164(6):2129–2133
Sakai S, Kawamura I, Okazaki T et al (2010) PD-1-PD-L1 pathway impairs Th1 immune response in the late stage of infection with Mycobacterium bovis bacillus Calmette-Guérin. Int Immunol 22(12):915–925. doi:10.1093/intimm/dxq446
Inman BA, Sebo TJ, Frigola X et al (2007) PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer 109(8):1499–1505. doi:10.1002/cncr.22588
Vandeveer AJ, Fallon JK, Tighe R et al (2016) Systemic immunotherapy of non-muscle invasive mouse bladder cancer with avelumab, an anti-PD-L1 immune checkpoint inhibitor. Cancer Immunol Res 4(5):452–462. doi:10.1158/2326-6066.CIR-15-0176
Powles T, Eder JP, Fine GD et al (2014) MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515(7528):558–562. doi:10.1038/nature13904
Rosenberg JE, Hoffman-Censits J, Powles T et al (2016) Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387(10031):1909–1920. doi:10.1016/S0140-6736(16)00561-4
Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507(7492):315–322. doi:10.1038/nature12965
Choi W, Porten S, Kim S et al (2014) Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25(2):152–165. doi:10.1016/j.ccr.2014.01.009
Damrauer JS, Hoadley KA, Chism DD et al (2014) Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci USA 111(8):3110–3115. doi:10.1073/pnas.1318376111
Choi W, Czerniak B, Ochoa A et al (2014) Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer. Nat Rev Urol 11(7):400–410. doi:10.1038/nrurol.2014.129
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Kojima, T., Kawai, K., Miyazaki, J. et al. Biomarkers for precision medicine in bladder cancer. Int J Clin Oncol 22, 207–213 (2017). https://doi.org/10.1007/s10147-016-1068-8
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DOI: https://doi.org/10.1007/s10147-016-1068-8