Investig Clin Urol.  2018 Mar;59(2):72-82. 10.4111/icu.2018.59.2.72.

Unmasking molecular profiles of bladder cancer

• Piao XM
• Byun YJ
• Kim WJ
• Kim J

• KMID: 2404975
• DOI: http://doi.org/10.4111/icu.2018.59.2.72

Abstract

Precision medicine is designed to tailor treatments for individual patients by factoring in each person's specific biology and mechanism of disease. This paradigm shifted from a "one size fits all" approach to "personalized and precision care" requires multiple layers of molecular profiling of biomarkers for accurate diagnosis and prediction of treatment responses. Intensive studies are also being performed to understand the complex and dynamic molecular profiles of bladder cancer. These efforts involve looking bladder cancer mechanism at the multiple levels of the genome, epigenome, transcriptome, proteome, lipidome, metabolome etc. The aim of this short review is to outline the current technologies being used to investigate molecular profiles and discuss biomarker candidates that have been investigated as possible diagnostic and prognostic indicators of bladder cancer.

Keyword

Biomarkers; Liquid biopsy; Precision medicine; Urinary bladder neoplasms

MeSH Terms

Biology
Biomarkers
Diagnosis
Genome
Humans
Metabolome
Precision Medicine
Proteome
Transcriptome
Urinary Bladder Neoplasms*
Urinary Bladder*
Biomarkers
Proteome

Figure

• 

  Fig. 1 A diagram showing current translational and clinical approaches to precision medicine for bladder cancer patients.

Reference

1. Diamandis M, White NM, Yousef GM. Personalized medicine: marking a new epoch in cancer patient management. Mol Cancer Res. 2010; 8:1175–1187.

2. Johnson DC, Greene PS, Nielsen ME. Surgical advances in bladder cancer: at what cost? Urol Clin North Am. 2015; 42:235–252. ix

3. Burger M, Catto JW, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013; 63:234–241.

4. Kaufman DS, Shipley WU, Feldman AS. Bladder cancer. Lancet. 2009; 374:239–249.

5. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005; 55:74–108.

6. Messing E. Markers of detection. Urol Oncol. 2007; 25:344–347.

7. Quan C, Cha EJ, Lee HL, Han KH, Lee KM, Kim WJ. Enhanced expression of peroxiredoxin I and VI correlates with development, recurrence and progression of human bladder cancer. J Urol. 2006; 175:1512–1516.

8. Bellmunt J, Pons F, Orsola A. Molecular determinants of response to cisplatin-based neoadjuvant chemotherapy. Curr Opin Urol. 2013; 23:466–471.

9. Kim J. Immune checkpoint blockade therapy for bladder cancer treatment. Investig Clin Urol. 2016; 57:Suppl 1. S98–105.

10. Lenis AT, Chamie K. Bladder cancer in 2014: from the genomic frontier to immunotherapeutics. Nat Rev Urol. 2015; 12:74–76.

11. Macleod LC, Ngo TC, Gonzalgo ML. Complications of intravesical bacillus calmette-guérin. Can Urol Assoc J. 2014; 8:E540–E544.

12. Steinberg RL, Thomas LJ, Nepple KG. Intravesical and alternative bladder-preservation therapies in the management of non-muscle-invasive bladder cancer unresponsive to bacillus Calmette-Guérin. Urol Oncol. 2016; 34:279–289.

13. Tomczak K, Czerwińska P, Wiznerowicz M. The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol (Pozn). 2015; 19:A68–A77.

14. Kim WJ, Kim YJ. Epigenetics of bladder cancer. Methods Mol Biol. 2012; 863:111–118.

15. Martínez-Fernández M, Rubio C, Segovia C, López-Calderón FF, Dueñas M, Paramio JM. EZH2 in bladder cancer, a promising therapeutic target. Int J Mol Sci. 2015; 16:27107–27132.

16. Wu CT, Lin WY, Chang YH, Lin PY, Chen WC, Chen MF. DNMT1-dependent suppression of microRNA424 regulates tumor progression in human bladder cancer. Oncotarget. 2015; 6:24119–24131.

17. Lombard AP, Mooso BA, Libertini SJ, Lim RM, Nakagawa RM, Vidallo KD, et al. miR-148a dependent apoptosis of bladder cancer cells is mediated in part by the epigenetic modifier DNMT1. Mol Carcinog. 2016; 55:757–767.

18. Palmbos PL, Wang L, Yang H, Wang Y, Leflein J, Ahmet ML, et al. ATDC/TRIM29 drives invasive bladder cancer formation through miRNA-mediated and epigenetic mechanisms. Cancer Res. 2015; 75:5155–5166.

19. Chen Z, Kim J. Urinary proteomics and metabolomics studies to monitor bladder health and urological diseases. BMC Urol. 2016; 16:11.

20. Di Meo A, Pasic MD, Yousef GM. Proteomics and peptidomics: moving toward precision medicine in urological malignancies. Oncotarget. 2016; 7:52460–52474.

21. Thomas S, Hao L, Ricke WA, Li L. Biomarker discovery in mass spectrometry-based urinary proteomics. Proteomics Clin Appl. 2016; 10:358–370.

22. Frantzi M, Latosinska A, Flühe L, Hupe MC, Critselis E, Kramer MW, et al. Developing proteomic biomarkers for bladder cancer: towards clinical application. Nat Rev Urol. 2015; 12:317–330.

23. Chan EC, Pasikanti KK, Hong Y, Ho PC, Mahendran R, Raman Nee Mani L, et al. Metabonomic profiling of bladder cancer. J Proteome Res. 2015; 14:587–602.

24. Deiss F, Mazzeo A, Hong E, Ingber DE, Derda R, Whitesides GM. Platform for high-throughput testing of the effect of soluble compounds on 3d cell cultures. Anal Chem. 2013; 85:8085–8094.

25. Håkanson M, Textor M, Charnley M. Engineered 3D environments to elucidate the effect of environmental parameters on drug response in cancer. Integr Biol (Camb). 2011; 3:31–38.

26. Gao D, Vela I, Sboner A, Iaquinta PJ, Karthaus WR, Gopalan A, et al. Organoid cultures derived from patients with advanced prostate cancer. Cell. 2014; 159:176–187.

27. Shariat SF, Savage C, Chromecki TF, Sun M, Scherr DS, Lee RK, et al. 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. 2011; 117:2892–2897.

28. Ho CC, Tan WP, Pathmanathan R, Tan WK, Tan HM. Fluorescence-in-situ-hybridization in the surveillance of urothelial cancers: can use of cystoscopy or ureteroscopy be deferred? Asian Pac J Cancer Prev. 2013; 14:4057–4059.

29. Gomella LG, Mann MJ, Cleary RC, Hubosky SG, Bagley DH, Thumar AB, et al. Fluorescence in situ hybridization (FISH) in the diagnosis of bladder and upper tract urothelial carcinoma: the largest single-institution experience to date. Can J Urol. 2017; 24:8620–8626.

30. Lavery HJ, Zaharieva B, McFaddin A, Heerema N, Pohar KS. A prospective comparison of UroVysion FISH and urine cytology in bladder cancer detection. BMC Cancer. 2017; 17:247.

31. Liem EIML, Baard J, Cauberg ECC, Bus MTJ, de Bruin DM, Laguna Pes MP, et al. Fluorescence in situ hybridization as prognostic predictor of tumor recurrence during treatment with Bacillus Calmette-Guérin therapy for intermediate- and high-risk non-muscle-invasive bladder cancer. Med Oncol. 2017; 34:172.

32. Virk RK, Abro S, de Ubago JMM, Pambuccian SE, Quek ML, Wojcik EM, et al. The value of the UroVysion® FISH assay in the risk-stratification of patients with “atypical urothelial cells” in urinary cytology specimens. Diagn Cytopathol. 2017; 45:481–500.

33. Yoshino H, Seki N, Itesako T, Chiyomaru T, Nakagawa M, Enokida H. Aberrant expression of microRNAs in bladder cancer. Nat Rev Urol. 2013; 10:396–404.

34. Yu J, Zhu T, Wang Z, Zhang H, Qian Z, Xu H, et al. A novel set of DNA methylation markers in urine sediments for sensitive/specific detection of bladder cancer. Clin Cancer Res. 2007; 13:7296–7304.

35. Vinci S, Giannarini G, Selli C, Kuncova J, Villari D, Valent F, et al. Quantitative methylation analysis of BCL2, hTERT, and DAPK promoters in urine sediment for the detection of nonmuscle-invasive urothelial carcinoma of the bladder: a prospective, two-center validation study. Urol Oncol. 2011; 29:150–156.

36. Ward DG, Baxter L, Gordon NS, Ott S, Savage RS, Beggs AD, et al. Multiplex PCR and next generation sequencing for the non-invasive detection of bladder cancer. PLoS One. 2016; 11:e0149756.

37. Kim J, Mouw KW, Polak P, Braunstein LZ, Kamburov A, Kwiatkowski DJ, et al. Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors. Nat Genet. 2016; 48:600–606.

38. Burns MB, Temiz NA, Harris RS. Evidence for APOBEC3B mutagenesis in multiple human cancers. Nat Genet. 2013; 45:977–983.

39. Nagata M, Muto S, Horie S. Molecular biomarkers in bladder cancer: novel potential indicators of prognosis and treatment outcomes. Dis Markers. 2016; 2016:8205836.

40. Zhang X, Zhang Y. Bladder cancer and genetic mutations. Cell Biochem Biophys. 2015; 73:65–69.

41. Nickerson ML, Witte N, Im KM, Turan S, Owens C, Misner K, et al. Molecular analysis of urothelial cancer cell lines for modeling tumor biology and drug response. Oncogene. 2017; 36:35–46.

42. Seiler R, Thalmann GN, Rotzer D, Perren A, Fleischmann A. CCND1/CyclinD1 status in metastasizing bladder cancer: a prognosticator and predictor of chemotherapeutic response. Mod Pathol. 2014; 27:87–95.

43. Dadhania V, Zhang M, Zhang L, Bondaruk J, Majewski T, Siefker-Radtke A, et al. Meta-analysis of the luminal and basal subtypes of bladder cancer and the identification of signature immunohistochemical markers for clinical use. EBioMedicine. 2016; 12:105–117.

44. Ross JS, Wang K, Al-Rohil RN, Nazeer T, Sheehan CE, Otto GA, et al. Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy. Mod Pathol. 2014; 27:271–280.

45. Ross JS, Wang K, Gay LM, Al-Rohil RN, Nazeer T, Sheehan CE, et al. A high frequency of activating extracellular domain ERBB2 (HER2) mutation in micropapillary urothelial carcinoma. Clin Cancer Res. 2014; 20:68–75.

46. Moss TJ, Qi Y, Xi L, Peng B, Kim TB, Ezzedine NE, et al. Comprehensive genomic characterization of upper tract urothelial carcinoma. Eur Urol. 2017; 72:641–649.

47. Pietzak EJ, Bagrodia A, Cha EK, Drill EN, Iyer G, Isharwal S, et al. Next-generation sequencing of nonmuscle invasive bladder cancer reveals potential biomarkers and rational therapeutic targets. Eur Urol. 2017; 72:952–959.

48. Choi W, Ochoa A, McConkey DJ, Aine M, Höglund M, Kim WY, et al. Genetic alterations in the molecular subtypes of bladder cancer: illustration in the cancer genome atlas dataset. Eur Urol. 2017; 72:354–365.

49. Abbosh PH, McConkey DJ, Plimack ER. Targeting signaling transduction pathways in bladder cancer. Curr Oncol Rep. 2015; 17:58.

50. Christensen E, Birkenkamp-Demtröder K, Nordentoft I, Høyer S, van der Keur K, van Kessel K, et al. Liquid biopsy analysis of FGFR3 and PIK3CA hotspot mutations for disease surveillance in bladder cancer. Eur Urol. 2017; 71:961–969.

51. Ding XL, Yang X, Liang G, Wang K. Isoform switching and exon skipping induced by the DNA methylation inhibitor 5-Aza-2′-deoxycytidine. Sci Rep. 2016; 6:24545.

52. Jenuwein T, Allis CD. Translating the histone code. Science. 2001; 293:1074–1080.

53. Kouzarides T. Chromatin modifications and their function. Cell. 2007; 128:693–705.

54. Gui Y, Guo G, Huang Y, Hu X, Tang A, Gao S, et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat Genet. 2011; 43:875–878.

55. Wolff EM, Byun HM, Han HF, Sharma S, Nichols PW, Siegmund KD, et al. Hypomethylation of a LINE-1 promoter activates an alternate transcript of the MET oncogene in bladders with cancer. PLoS Genet. 2010; 6:e1000917.

56. Kim EJ, Kim YJ, Jeong P, Ha YS, Bae SC, Kim WJ. Methylation of the RUNX3 promoter as a potential prognostic marker for bladder tumor. J Urol. 2008; 180:1141–1145.

57. Costa-Pinheiro P, Montezuma D, Henrique R, Jerónimo C. Diagnostic and prognostic epigenetic biomarkers in cancer. Epigenomics. 2015; 7:1003–1015.

58. Maruyama R, Toyooka S, Toyooka KO, Harada K, Virmani AK, Zöchbauer-Müller S, et al. Aberrant promoter methylation profile of bladder cancer and its relationship to clinicopathological features. Cancer Res. 2001; 61:8659–8663.

59. Marsit CJ, Karagas MR, Andrew A, Liu M, Danaee H, Schned AR, et al. Epigenetic inactivation of SFRP genes and TP53 alteration act jointly as markers of invasive bladder cancer. Cancer Res. 2005; 65:7081–7085.

60. Catto JW, Azzouzi AR, Rehman I, Feeley KM, Cross SS, Amira N, et al. Promoter hypermethylation is associated with tumor location, stage, and subsequent progression in transitional cell carcinoma. J Clin Oncol. 2005; 23:2903–2910.

61. Su SF, de Castro Abreu AL, Chihara Y, Tsai Y, Andreu-Vieyra C, Daneshmand S, et al. A panel of three markers hyper- and hypomethylated in urine sediments accurately predicts bladder cancer recurrence. Clin Cancer Res. 2014; 20:1978–1989.

62. Ratliff TL, Gillen D, Catalona WJ. Requirement of a thymus dependent immune response for BCG-mediated antitumor activity. J Urol. 1987; 137:155–158.

63. Sweis RF, Galsky MD. Emerging role of immunotherapy in urothelial carcinoma-immunobiology/biomarkers. Urol Oncol. 2016; 34:556–565.

64. Donin NM, Lenis AT, Holden S, Drakaki A, Pantuck A, Belldegrun A, et al. Immunotherapy for the treatment of urothelial carcinoma. J Urol. 2017; 197:14–22.

65. Bitler BG, Aird KM, Garipov A, Li H, Amatangelo M, Kossenkov AV, et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med. 2015; 21:231–238.

66. Balbás-Martínez C, Rodríguez-Pinilla M, Casanova A, Domínguez O, Pisano DG, Gómez G, et al. ARID1A alterations are associated with FGFR3-wild type, poor-prognosis, urothelial bladder tumors. PLoS One. 2013; 8:e62483.

67. Scott SN, Ostrovnaya I, Lin CM, Bouvier N, Bochner BH, Iyer G, et al. Next-generation sequencing of urine specimens: a novel platform for genomic analysis in patients with nonmuscle-invasive urothelial carcinoma treated with bacille Calmette-Guérin. Cancer Cytopathol. 2017; 125:416–426.

68. Kreunin P, Zhao J, Rosser C, Urquidi V, Lubman DM, Goodison S. Bladder cancer associated glycoprotein signatures revealed by urinary proteomic profiling. J Proteome Res. 2007; 6:2631–2639.

69. Li H, Li C, Wu H, Zhang T, Wang J, Wang S, et al. Identification of Apo-A1 as a biomarker for early diagnosis of bladder transitional cell carcinoma. Proteome Sci. 2011; 9:21.

70. Li F, Chen DN, He CW, Zhou Y, Olkkonen VM, He N, et al. Identification of urinary Gc-globulin as a novel biomarker for bladder cancer by two-dimensional fluorescent differential gel electrophoresis (2D-DIGE). J Proteomics. 2012; 77:225–236.

71. Orenes-Piñero E, Barderas R, Rico D, Casal JI, Gonzalez-Pisano D, Navajo J, et al. Serum and tissue profiling in bladder cancer combining protein and tissue arrays. J Proteome Res. 2010; 9:164–173.

72. Urquidi V, Chang M, Dai Y, Kim J, Wolfson ED, Goodison S, et al. Il-8 as a urinary biomarker for the detection of bladder cancer. BMC Urol. 2012; 12:12.

73. Srinivasan H, Allory Y, Sill M, Vordos D, Alhamdani MS, Radvanyi F, et al. Prediction of recurrence of non muscle-invasive bladder cancer by means of a protein signature identified by antibody microarray analyses. Proteomics. 2014; 14:1333–1342.

74. Grau L, Luque-Garcia JL, González-Peramato P, Theodorescu D, Palou J, Fernandez-Gomez JM, et al. A quantitative proteomic analysis uncovers the relevance of CUL3 in bladder cancer aggressiveness. PLoS One. 2013; 8:e53328.

75. Bansal N, Gupta A, Sankhwar SN, Mahdi AA. Low- and high-grade bladder cancer appraisal via serum-based proteomics approach. Clin Chim Acta. 2014; 436:97–103.

76. Cheng Y, Yang X, Deng X, Zhang X, Li P, Tao J, et al. Metabolomics in bladder cancer: a systematic review. Int J Clin Exp Med. 2015; 8:11052–11063.

77. von Rundstedt FC, Rajapakshe K, Ma J, Arnold JM, Gohlke J, Putluri V, et al. Integrative pathway analysis of metabolic signature in bladder cancer: a linkage to the cancer genome atlas project and prediction of survival. J Urol. 2016; 195:1911–1919.

78. Bansal N, Gupta A, Mitash N, Shakya PS, Mandhani A, Mahdi AA, et al. Low- and high-grade bladder cancer determination via human serum-based metabolomics approach. J Proteome Res. 2013; 12:5839–5850.

79. Cao M, Zhao L, Chen H, Xue W, Lin D. NMR-based metabolomic analysis of human bladder cancer. Anal Sci. 2012; 28:451–456.

80. Jin X, Yun SJ, Jeong P, Kim IY, Kim WJ, Park S. Diagnosis of bladder cancer and prediction of survival by urinary metabolomics. Oncotarget. 2014; 5:1635–1645.

81. Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer. 2015; 15:25–41.

82. Dyrskjøt L, Zieger K, Kruhøffer M, Thykjaer T, Jensen JL, Primdahl H, et al. A molecular signature in superficial bladder carcinoma predicts clinical outcome. Clin Cancer Res. 2005; 11:4029–4036.

83. Sjödahl G, Lauss M, Lövgren K, Chebil G, Gudjonsson S, Veerla S, et al. A molecular taxonomy for urothelial carcinoma. Clin Cancer Res. 2012; 18:3377–3386.

84. Yang M, Zheng Z, Zhuang Z, Zhao X, Xu Z, Lin H. Immuno-Cyt™ and cytology for diagnosis of bladder carcinoma: a meta analysis. Chin Med J (Engl). 2014; 127:758–764.

85. Siemens DR, Morales A, Johnston B, Emerson L. A comparative analysis of rapid urine tests for the diagnosis of upper urinary tract malignancy. Can J Urol. 2003; 10:1754–1758.

86. Naoe M, Ogawa Y, Morita J, Omori K, Takeshita K, Shichijyo T, et al. Detection of circulating urothelial cancer cells in the blood using the CellSearch System. Cancer. 2007; 109:1439–1445.

87. Flaig TW, Wilson S, van Bokhoven A, Varella-Garcia M, Wolfe P, Maroni P, et al. Detection of circulating tumor cells in metastatic and clinically localized urothelial carcinoma. Urology. 2011; 78:863–867.

88. Qi F, Liu Y, Zhao R, Zou X, Zhang L, Li J, et al. Quantitation of rare circulating tumor cells by folate receptor α ligand-targeted PCR in bladder transitional cell carcinoma and its potential diagnostic significance. Tumour Biol. 2014; 35:7217–7223.

89. Anantharaman A, Friedlander T, Lu D, Krupa R, Premasekharan G, Hough J, et al. Programmed death-ligand 1 (PD-L1) characterization of circulating tumor cells (CTCs) in muscle invasive and metastatic bladder cancer patients. BMC Cancer. 2016; 16:744.

90. Zhang T, Boominathan R, Foulk B, Rao C, Kemeny G, Strickler JH, et al. Development of a novel c-MET-based CTC detection platform. Mol Cancer Res. 2016; 14:539–547.

91. Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013; 10:472–484.

92. Kinde I, Munari E, Faraj SF, Hruban RH, Schoenberg M, Bivalacqua T, et al. TERT promoter mutations occur early in urothelial neoplasia and are biomarkers of early disease and disease recurrence in urine. Cancer Res. 2013; 73:7162–7167.

93. Gormally E, Vineis P, Matullo G, Veglia F, Caboux E, Le Roux E, et al. TP53 and KRAS2 mutations in plasma DNA of healthy subjects and subsequent cancer occurrence: a prospective study. Cancer Res. 2006; 66:6871–6876.

94. Fernandez-Mercado M, Manterola L, Larrea E, Goicoechea I, Arestin M, Armesto M, et al. The circulating transcriptome as a source of non-invasive cancer biomarkers: concepts and controversies of non-coding and coding RNA in body fluids. J Cell Mol Med. 2015; 19:2307–2323.

95. Malentacchi F, Vinci S, Melina AD, Kuncova J, Villari D, Nesi G, et al. Urinary carbonic anhydrase IX splicing messenger RNA variants in urogenital cancers. Urol Oncol. 2016; 34:292.e9–292.e16.

96. Xie XY, Yang X, Zhang JH, Liu ZJ. Analysis of hTERT expression in exfoliated cells from patients with bladder transitional cell carcinomas using SYBR green real-time fluorescence quantitative PCR. Ann Clin Biochem. 2007; 44:523–528.

97. Sasaki H, Yoshiike M, Nozawa S, Usuba W, Katsuoka Y, Aida K, et al. Expression level of urinary MicroRNA-146a-5p is increased in patients with bladder cancer and decreased in those after transurethral resection. Clin Genitourin Cancer. 2016; 14:e493–e499.

98. Yu S, Cao H, Shen B, Feng J. Tumor-derived exosomes in cancer progression and treatment failure. Oncotarget. 2015; 6:37151–37168.

99. Nawaz M, Camussi G, Valadi H, Nazarenko I, Ekström K, Wang X, et al. The emerging role of extracellular vesicles as biomarkers for urogenital cancers. Nat Rev Urol. 2014; 11:688–701.

100. Berrondo C, Flax J, Kucherov V, Siebert A, Osinski T, Rosenberg A, et al. Expression of the long non-coding RNA HOTAIR correlates with disease progression in bladder cancer and is contained in bladder cancer patient urinary exosomes. PLoS One. 2016; 11:e0147236.