Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Approaches to urinary detection of prostate cancer

Prostate Cancer and Prostatic Diseases volume 22, pages 362–381 (2019)Cite this article

Subjects

Abstract

Background

Prostate cancer is the most common cancer in American men that ranges from low risk states amenable to active surveillance to high-risk states that can be lethal especially if untreated. There is a critical need to develop relatively non-invasive and clinically useful methods for screening, detection, prognosis, disease monitoring, and prediction of treatment efficacy. In this review, we focus on important advances as well as future efforts needed to drive clinical innovation in this area of urine biomarker research for prostate cancer detection and prognostication.

Methods

We provide a review of current literature on urinary biomarkers for prostate cancer. We evaluate the strengths and limitations of a variety of approaches that vary in sampling strategies and targets measured; discuss reported urine tests for prostate cancer with respect to their technical, analytical, and clinical parameters; and provide our perspectives on critical considerations in approaches to developing a urine-based test for prostate cancer.

Results

There has been an extensive history of exploring urine as a source of biomarkers for prostate cancer that has resulted in a variety of urine tests that are in current clinical use. Importantly, at least three tests have demonstrated high sensitivity (~90%) and negative predictive value (~95%) for clinically significant tumors; however, there has not been widespread adoption of these tests.

Conclusions

Conceptual and methodological advances in the field will help to drive the development of novel urinary tests that in turn may lead to a shift in the clinical paradigm for prostate cancer diagnosis and management.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Stamey TA, Yang N, Hay AR, McNeal JE, Freiha FS, Redwine E. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med. 1987;317:909–16.

    Article  CAS  PubMed  Google Scholar 

  2. Lilja H, Ulmert D, Vickers AJ. Prostate-specific antigen and prostate cancer: prediction, detection and monitoring. Nat Rev Cancer. 2008;8:268.

    Article  CAS  PubMed  Google Scholar 

  3. Blute ML Jr, Abel EJ, Downs TM, Kelcz F, Jarrard DF. Addressing the need for repeat prostate biopsy: new technology and approaches. Nat Rev Urol. 2015;12:435.

    Article  PubMed  Google Scholar 

  4. Julian BA, Suzuki H, Suzuki Y, Tomino Y, Spasovski G, Novak J. Sources of urinary proteins and their analysis by urinary proteomics for the detection of biomarkers of disease. Proteom Clin Appl. 2009;3:1029–43.

    Article  CAS  Google Scholar 

  5. Emwas AH, Luchinat C, Turano P, Tenori L, Roy R, Salek RM, et al. Standardizing the experimental conditions for using urine in NMR-based metabolomic studies with a particular focus on diagnostic studies: a review. Metabolomics. 2015;11:872–94.

    Article  CAS  PubMed  Google Scholar 

  6. Prensner JR, Rubin MA, Wei JT, Chinnaiyan AM. Beyond PSA: the next generation of prostate cancer biomarkers. Sci Transl Med. 2012;4:127–123.

    Article  CAS  Google Scholar 

  7. Kavanagh JP, Darby C, Costello CB. The response of seven prostatic fluid components to prostatic disease. Int J Androl. 1982;5:487–96.

    Article  CAS  PubMed  Google Scholar 

  8. McCallum KA, Kavanagh JP, Farragher EB, Blacklock NJ. Ratio of post-prostatic massage urinary zinc concentration to initial urinary zinc concentration. Improv Method Assess prostatic Funct Br J Urol. 1988;62:565–70.

    CAS  Google Scholar 

  9. Scott WW, Huggins C. The acid phosphatase activity of human urine, an index of prostatic secretion. Endocrinology. 1942;30:107–12.

    Article  CAS  Google Scholar 

  10. Breul J, Pickl U, Hartung R. Prostate-specific antigen in urine. Eur Urol. 1994;26:18–21.

    Article  CAS  PubMed  Google Scholar 

  11. Daniel O, Kind PRN, King EJ. Urinary excretion of acid phosphatase. BMJ. 1954;1:19–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Moberg PJ, Lizana J, Eneroth P. Analysis of prostatic acid phosphatase in urine voided before and after massage of theprostate in infertile men. Urol Int. 1984;39:189–92.

    Article  CAS  PubMed  Google Scholar 

  13. Grayhack JT, Lee C, Oliver L, Schaeffer AJ, Wendel EF. Biochemical profiles of prostatic fluid from normal and diseased prostate glands. Prostate. 1980;1:227–37.

    Article  CAS  PubMed  Google Scholar 

  14. Costello LC, Franklin RB. Prostatic fluid electrolyte composition for the screening of prostate cancer: a potential solution to a major problem. Prostate Cancer Prostatic Dis. 2009;12:17–24.

    Article  CAS  PubMed  Google Scholar 

  15. Costello LC, Franklin RB. A comprehensive review of the role of zinc in normal prostate function and metabolism; and its implications in prostate cancer. Arch Biochem Biophys. 2016;611:100–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Medarova Z, Ghosh SK, Vangel M, Drake R, Moore A. Risk stratification of prostate cancer patients based on EPS-urine zinc content. Am J Cancer Res. 2014;4:385–93.

    PubMed  PubMed Central  Google Scholar 

  17. Zhang X-a, Hayes D, Smith SJ, Friedle S, Lippard SJ. New strategy for quantifying biological zinc by a modified zinpyr fluorescence sensor. J Am Chem Soc. 2008;130:15788–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lima AR, Bastos Mde L, Carvalho M, Guedes de Pinho P. Biomarker discovery in human prostate cancer: an update in metabolomics studies. Transl Oncol. 2016;9:357–70.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kelly RS, Vander Heiden MG, Giovannucci E, Mucci LA. Metabolomic biomarkers of prostate cancer: prediction, diagnosis, progression, prognosis, and recurrence. Cancer Epidemiol, Biomark Prev. 2016;25:887–906.

    Article  CAS  Google Scholar 

  20. Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009;457:910–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jentzmik F, Stephan C, Miller K, Schrader M, Erbersdobler A, Kristiansen G, et al. Sarcosine in urine after digital rectal examination fails as a marker in prostate cancer detection and identification of aggressive tumours. Eur Urol. 2010;58:12–18.

    Article  CAS  PubMed  Google Scholar 

  22. Wu H, Liu T, Ma C, Xue R, Deng C, Zeng H, et al. GC/MS-based metabolomic approach to validate the role of urinary sarcosine and target biomarkers for human prostate cancer by microwave-assisted derivatization. Anal Bioanal Chem. 2011;401:635–46.

    Article  CAS  PubMed  Google Scholar 

  23. Cao DL, Ye DW, Zhu Y, Zhang HL, Wang YX, Yao XD. Efforts to resolve the contradictions in early diagnosis of prostate cancer: a comparison of different algorithms of sarcosine in urine. Prostate Cancer Prostatic Dis. 2011;14:166–72.

    Article  CAS  PubMed  Google Scholar 

  24. Jiang Y, Cheng X, Wang C, Ma Y. Quantitative determination of sarcosine and related compounds in urinary samples by liquid chromatography with tandem mass spectrometry. Anal Chem. 2010;82:9022–7.

    Article  CAS  PubMed  Google Scholar 

  25. Issaq HJ, Veenstra TD. Is sarcosine a biomarker for prostate cancer?. J Sep Sci. 2011;34:3619–21.

    Article  CAS  PubMed  Google Scholar 

  26. Shirasu M, Touhara K. The scent of disease: volatile organic compounds of the human body related to disease and disorder. J Biochem. 2011;150:257–66.

    Article  CAS  PubMed  Google Scholar 

  27. Gordon RT, Schatz CB, Myers LJ, Kosty M, Gonczy C, Kroener J, et al. The use of canines in the detection of human cancers. J Altern Complement Med (New Y, NY). 2008;14:61–67.

    Article  Google Scholar 

  28. Cornu JN, Cancel-Tassin G, Ondet V, Girardet C, Cussenot O. Olfactory detection of prostate cancer by dogs sniffing urine: a step forward in early diagnosis. Eur Urol. 2011;59:197–201.

    Article  PubMed  Google Scholar 

  29. Taverna G, Tidu L, Grizzi F, Torri V, Mandressi A, Sardella P, et al. Olfactory system of highly trained dogs detects prostate cancer in urine samples. J Urol. 2015;193:1382–7.

    Article  CAS  PubMed  Google Scholar 

  30. Elliker KR, Sommerville BA, Broom DM, Neal DE, Armstrong S, Williams HC. Key considerations for the experimental training and evaluation of cancer odour detection dogs: lessons learnt from a double-blind, controlled trial of prostate cancer detection. BMC Urol. 2014;14:22.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lippi G, Cervellin G. Canine olfactory detection of cancer versus laboratory testing: myth or opportunity?. Clin Chem Lab Med. 2012;50:435–9.

    CAS  PubMed  Google Scholar 

  32. Jezierski T, Walczak M, Ligor T, Rudnicka J, Buszewski B. Study of the art: canine olfaction used for cancer detection on the basis of breath odour. Perspectives and limitations. J Breath Res. 2015;9:027001.

    Article  PubMed  CAS  Google Scholar 

  33. Hackner K, Pleil J. Canine olfaction as an alternative to analytical instruments for disease diagnosis: understanding ‘dog personality’ to achieve reproducible results. J Breath Res. 2017;11:012001.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Pirrone F, Albertini M. Olfactory detection of cancer by trained sniffer dogs: a systematic review of the literature. J Vet Behav: Clin Appl Res. 2017;19:105–17.

    Article  Google Scholar 

  35. Bax C, Taverna G, Eusebio L, Sironi S, Grizzi F, Guazzoni G, et al. Innovative diagnostic methods for early prostate cancer detection through urine analysis: a review. Cancers. 2018, 10: pii: E123.

    Article  PubMed Central  CAS  Google Scholar 

  36. Bernabei M, Pennazza G, Santonico M, Corsi C, Roscioni C, Paolesse R, et al. A preliminary study on the possibility to diagnose urinary tract cancers by an electronic nose. Sens Actuators B. 2008;131:1–4.

    Article  CAS  Google Scholar 

  37. Roine A, Veskimae E, Tuokko A, Kumpulainen P, Koskimaki J, Keinanen TA, et al. Detection of prostate cancer by an electronic nose: a proof of principle study. J Urol. 2014;192:230–4.

    Article  PubMed  Google Scholar 

  38. Asimakopoulos AD, Del Fabbro D, Miano R, Santonico M, Capuano R, Pennazza G, et al. Prostate cancer diagnosis through electronic nose in the urine headspace setting: a pilot study. Prostate Cancer Prostatic Dis. 2014;17:206–11.

    Article  CAS  PubMed  Google Scholar 

  39. Krishnan B, Truong LD. Prostatic adenocarcinoma diagnosed by urinary cytology. Am J Clin Pathol. 2000;113:29–34.

    Article  CAS  PubMed  Google Scholar 

  40. Tyler KL, Selvaggi SM. Morphologic features of prostatic adenocarcinoma on ThinPrep(R) urinary cytology. Diagn Cytopathol. 2011;39:101–4.

    Article  PubMed  Google Scholar 

  41. Varma VA, Fekete PS, Franks MJ, Walther MM. Cytologic features of prostatic adenocarcinoma in urine: a clinicopathologic and immunocytochemical study. Diagn Cytopathol. 1988;4:300–5.

    Article  CAS  PubMed  Google Scholar 

  42. Seybolt JF. Cytology of the urinary tract and prostate. CA Cancer J Clin. 1960;10:129–39.

    Article  CAS  PubMed  Google Scholar 

  43. Sharifi R, Shaw M, Ray V, Rhee H, Nagubadi S, Guinan P. Evaluation of cytologic techniques for diagnosis of prostate cancer. Urology. 1983;21:417–20.

    Article  CAS  PubMed  Google Scholar 

  44. Foot NC, Papanicolaou GN, Holmquist ND, Seybolt JF. Exfoliative cytology of urinary sediments; a review of 2,829 cases. Cancer. 1958;11:127–37.

    Article  CAS  PubMed  Google Scholar 

  45. Nickens KP, Ali A, Scoggin T, Tan SH, Ravindranath L, McLeod DG, et al. Prostate cancer marker panel with single cell sensitivity in urine. Prostate. 2015;75:969–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kobayashi TK, Ueda M, Yamaki T, Yakushiji M. Evaluation of cytocentrifuge apparatus with special reference to the cellular recovery rate. Diagn Cytopathol. 1992;8:420–3.

    Article  CAS  PubMed  Google Scholar 

  47. Echeverry G, Hortin GL, Rai AJ. Introduction to urinalysis: historical perspectives and clinical application. Methods Mol Biol (Clifton, NJ). 2010;641:1–12.

    Article  CAS  Google Scholar 

  48. Rupp M, O’Hara B, McCullough L, Saxena S, Olchiewski J. Prostatic carcinoma cells in urine specimens. Cytopathology. 1994;5:164–70.

    Article  CAS  PubMed  Google Scholar 

  49. Fujita K, Pavlovich CP, Netto GJ, Konishi Y, Isaacs WB, Ali S, et al. Specific detection of prostate cancer cells in urine by multiplex immunofluorescence cytology. Hum Pathol. 2009;40:924–33.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Ralla B, Stephan C, Meller S, Dietrich D, Kristiansen G, Jung K. Nucleic acid-based biomarkers in body fluids of patients with urologic malignancies. Crit Rev Clin Lab Sci. 2014;51:200–31.

    Article  CAS  PubMed  Google Scholar 

  51. Tzimagiorgis G, Michailidou EZ, Kritis A, Markopoulos AK, Kouidou S. Recovering circulating extracellular or cell-free RNA from bodily fluids. Cancer Epidemiol. 2011;35:580–9.

    Article  CAS  PubMed  Google Scholar 

  52. Hendriks RJ, van Oort IM, Schalken JA. Blood-based and urinary prostate cancer biomarkers: a review and comparison of novel biomarkers for detection and treatment decisions. Prostate Cancer Prostatic Dis. 2017;20:12–19.

    Article  CAS  PubMed  Google Scholar 

  53. Martignano F, Rossi L, Maugeri A, Galla V, Conteduca V, De Giorgi U, et al. Urinary RNA-based biomarkers for prostate cancer detection. Clin Chim Acta. 2017;473:96–105.

    Article  CAS  PubMed  Google Scholar 

  54. Bussemakers MJ, van Bokhoven A, Verhaegh GW, Smit FP, Karthaus HF, Schalken JA, et al. DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res. 1999;59:5975–9.

    CAS  PubMed  Google Scholar 

  55. Sanguedolce F, Cormio A, Brunelli M, D’Amuri A, Carrieri G, Bufo P, et al. Urine TMPRSS2: ERG fusion transcript as a biomarker for prostate cancer: literature review. Clin Genitourin Cancer. 2016;14:117–21.

    Article  PubMed  Google Scholar 

  56. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Sci (New Y, NY). 2005;310:644–8.

    Article  CAS  Google Scholar 

  57. Laxman B, Tomlins SA, Mehra R, Morris DS, Wang L, Helgeson BE, et al. Noninvasive detection of TMPRSS2:ERG fusion transcripts in the urine of men with prostate cancer. Neoplasia. 2006;8:885–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rogers CG, Yan G, Zha S, Gonzalgo ML, Isaacs WB, Luo J, et al. Prostate cancer detection on urinalysis for alpha methylacyl coenzyme a racemase protein. J Urol. 2004;172:1501–3.

    Article  CAS  PubMed  Google Scholar 

  59. Zehentner BK, Secrist H, Zhang X, Hayes DC, Ostenson R, Goodman G, et al. Detection of alpha-methylacyl-coenzyme-A racemase transcripts in blood and urine samples of prostate cancer patients. Mol Diagn Ther. 2006;10:397–403.

    Article  CAS  PubMed  Google Scholar 

  60. Laxman B, Morris DS, Yu J, Siddiqui J, Cao J, Mehra R, et al. A first-generation multiplex biomarker analysis of urine for the early detection of prostate cancer. Cancer Res. 2008;68:645–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Varambally S, Laxman B, Mehra R, Cao Q, Dhanasekaran SM, Tomlins SA, et al. Golgi protein GOLM1 is a tissue and urine biomarker of prostate cancer. Neoplasia. 2008;10:1285–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Crocitto LE, Korns D, Kretzner L, Shevchuk T, Blair SL, Wilson TG, et al. Prostate cancer molecular markers GSTP1 and hTERT in expressed prostatic secretions as predictors of biopsy results. Urology. 2004;64:821–5.

    Article  PubMed  Google Scholar 

  63. Meid FH, Gygi CM, Leisinger HJ, Bosman FT, Benhattar J. The use of telomerase activity for the detection of prostatic cancer cells after prostatic massage. J Urol. 2001;165:1802–5.

    Article  CAS  PubMed  Google Scholar 

  64. Leyten GH, Hessels D, Smit FP, Jannink SA, de Jong H, Melchers WJ, et al. Identification of a candidate gene panel for the early diagnosis of prostate cancer. Clin Cancer Res. 2015;21:3061–70.

    Article  CAS  PubMed  Google Scholar 

  65. Van Neste L, Hendriks RJ, Dijkstra S, Trooskens G, Cornel EB, Jannink SA, et al. Detection of high-grade prostate cancer using a urinary molecular biomarker–based risk score. Eur Urol. 2016;70:740–8.

    Article  CAS  PubMed  Google Scholar 

  66. Rigau M, Ortega I, Mir MC, Ballesteros C, Garcia M, Llaurado M, et al. A three-gene panel on urine increases PSA specificity in the detection of prostate cancer. Prostate. 2011;71:1736–45.

    Article  CAS  PubMed  Google Scholar 

  67. Rigau M, Olivan M, Garcia M, Sequeiros T, Montes M, Colas E, et al. The present and future of prostate cancer urine biomarkers. Int J Mol Sci. 2013;14:12620–49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Jamaspishvili T, Kral M, Khomeriki I, Vyhnankova V, Mgebrishvili G, Student V, et al. Quadriplex model enhances urine-based detection of prostate cancer. Prostate Cancer Prostatic Dis. 2011;14:354–60.

    Article  CAS  PubMed  Google Scholar 

  69. Ouyang B, Bracken B, Burke B, Chung E, Liang J, Ho SM. A duplex quantitative polymerase chain reaction assay based on quantification of alpha-methylacyl-CoA racemase transcripts and prostate cancer antigen 3 in urine sediments improved diagnostic accuracy for prostate cancer. J Urol. 2009;181:2508–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Salami SS, Schmidt F, Laxman B, Regan MM, Rickman DS, Scherr D, et al. Combining urinary detection of TMPRSS2:ERG and PCA3 with serum PSA to predict diagnosis of prostate cancer. Urol Oncol. 2013;31:566–71.

    Article  CAS  PubMed  Google Scholar 

  71. Larsen LK, Jakobsen JS, Abdul-Al A, Guldberg P. Noninvasive detection of high grade prostate cancer by dna methylation analysis of urine cells captured by microfiltration. J Urol. 2018;200:749–57.

    Article  CAS  PubMed  Google Scholar 

  72. Sokoll LJ, Ellis W, Lange P, Noteboom J, Elliott DJ, Deras IL, et al. A multicenter evaluation of the PCA3 molecular urine test: pre-analytical effects, analytical performance, and diagnostic accuracy. Clin Chim Acta. 2008;389:1–6.

    Article  CAS  PubMed  Google Scholar 

  73. Shappell SB, Fulmer J, Arguello D, Wright BS, Oppenheimer JR, Putzi MJ. PCA3 urine mRNA testing for prostate carcinoma: patterns of use by community urologists and assay performance in reference laboratory setting. Urology. 2009;73:363–8.

    Article  PubMed  Google Scholar 

  74. Wang G, Szeto C-C. Quantification of gene expression in urinary sediment for the study of renal diseases. Nephrology. 2007;12:494–9.

    Article  CAS  PubMed  Google Scholar 

  75. Casadio V, Calistri D, Salvi S, Gunelli R, Carretta E, Amadori D, et al. Urine cell-free DNA integrity as a marker for early prostate cancer diagnosis: a pilot study. Biomed Res Int. 2013;2013:270457.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Rykova EY, Morozkin ES, Ponomaryova AA, Loseva EM, Zaporozhchenko IA, Cherdyntseva NV, et al. Cell-free and cell-bound circulating nucleic acid complexes: mechanisms of generation, concentration and content. Expert Opin Biol Ther. 2012;12(sup1):S141–S153.

    Article  CAS  PubMed  Google Scholar 

  77. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200:373–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Crescitelli R, Lasser C, Szabo TG, Kittel A, Eldh M, Dianzani I, et al. Distinct RNA profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes. J Extracell Vesicles. 2013;2:eCollection 2013.

    Article  CAS  Google Scholar 

  79. Principe S, Jones EE, Kim Y, Sinha A, Nyalwidhe JO, Brooks J, et al. In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. Proteomics. 2013;13:1667–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. McKiernan J, Donovan MJ, O’Neill V, Bentink S, Noerholm M, Belzer S, et al. A novel urine exosome gene expression assay to predict high-grade prostate cancer at initial biopsy. JAMA Oncol. 2016;2:882–9.

    Article  PubMed  Google Scholar 

  81. Zhou H, Yuen PS, Pisitkun T, Gonzales PA, Yasuda H, Dear JW, et al. Collection, storage, preservation, and normalization of human urinary exosomes for biomarker discovery. Kidney Int. 2006;69:1471–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Royo F, Zuñiga-Garcia P, Sanchez-Mosquera P, Egia A, Perez A, Loizaga A, et al. Different EV enrichment methods suitable for clinical settings yield different subpopulations of urinary extracellular vesicles from human samples. J Extracell Vesicles 2016, 5:https://doi.org/10.3402/jev.v3405.29497.

  83. Harpole M, Davis J, Espina V. Current state of the art for enhancing urine biomarker discovery. Expert Rev Proteom. 2016;13:609–26.

    Article  CAS  Google Scholar 

  84. Adachi J, Kumar C, Zhang Y, Olsen JV, Mann M. The human urinary proteome contains more than 1500 proteins, including a large proportion of membrane proteins. Genome Biol. 2006;7:R80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Thomas S, Hao L, Ricke WA, Li L. Biomarker discovery in mass spectrometry-based urinary proteomics. Proteom Clin Appl. 2016;10:358–70.

    Article  CAS  Google Scholar 

  86. Nagaraj N, Mann M. Quantitative analysis of the intra- and inter-individual variability of the normal urinary proteome. J Proteome Res. 2011;10:637–45.

    Article  CAS  PubMed  Google Scholar 

  87. Pisitkun T, Johnstone R, Knepper MA. Discovery of urinary biomarkers. Mol Cell Proteom. 2006;5:1760–71.

    Article  CAS  Google Scholar 

  88. Decramer S, Gonzalez de Peredo A, Breuil B, Mischak H, Monsarrat B, Bascands JL, et al. Urine in clinical proteomics. Mol Cell Proteom. 2008;7:1850–62.

    Article  CAS  Google Scholar 

  89. Hendriks Rianne J, Dijkstra S, Jannink Sander A, Steffens Martijn G, van Oort Inge M, Mulders Peter FA, et al. Comparative analysis of prostate cancer specific biomarkers PCA3 and ERG in whole urine, urinary sediments and exosomes. Clin Chem Lab Med. 2016;54:483.

    Article  CAS  PubMed  Google Scholar 

  90. Donovan MJ, Noerholm M, Bentink S, Belzer S, Skog J, O’Neill V, et al. A molecular signature of PCA3 and ERG exosomal RNA from non-DRE urine is predictive of initial prostate biopsy result. Prostate Cancer Prostatic Dis. 2015;18:370–5.

    Article  CAS  PubMed  Google Scholar 

  91. Nilsson J, Skog J, Nordstrand A, Baranov V, Mincheva-Nilsson L, Breakefield XO, et al. Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer. Br J Cancer. 2009;100:1603–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR, Humphrey PA. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: Definition of Grading Patterns and Proposal for a New Grading System. Am J Surg Pathol. 2016;40:244–52.

    Article  PubMed  Google Scholar 

  93. Truong M, Frye T, Messing E, Miyamoto H. Historical and contemporary perspectives on cribriform morphology in prostate cancer. Nat Rev Urol. 2018;15:475–82.

    Article  PubMed  Google Scholar 

  94. Deras IL, Aubin SM, Blase A, Day JR, Koo S, Partin AW, et al. PCA3: a molecular urine assay for predicting prostate biopsy outcome. J Urol. 2008;179:1587–92.

    Article  PubMed  Google Scholar 

  95. Wei JT, Feng Z, Partin AW, Brown E, Thompson I, Sokoll L, et al. Can urinary PCA3 supplement PSA in the early detection of prostate cancer?. J Clin Oncol. 2014;32:4066–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Sanda MG, Feng Z, Howard DH, et al. Association between combined TMPRSS2:ERG and PCA3 RNA urinary testing and detection of aggressive prostate cancer. JAMA Oncol. 2017;3:1085–93.

    Article  PubMed  PubMed Central  Google Scholar 

  97. McDunn JE, Li Z, Adam K-P, Neri BP, Wolfert RL, Milburn MV, et al. Metabolomic signatures of aggressive prostate cancer. Prostate. 2013;73:1547–60.

    Article  CAS  PubMed  Google Scholar 

  98. McDunn JE, Stirdivant SM, Ford LA, Wolfert RL. Metabolomics and its application to the development of clinical laboratory tests for prostate cancer. EJIFCC. 2015;26:92–104.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. D’Amico A, Santonico M, Pennazza G, Capuano R, Vespasiani G, Del Fabbro D, et al. Approach for prostate cancer diagnosis using a gas sensor array. Procedia Eng. 2012;47:1113–6.

    Article  CAS  Google Scholar 

  100. Santonico M, Pennazza G, Asimakopoulos AD, Del Fabbro D, Miano R, Capuano R, et al. Chemical sensors for prostate cancer detection oriented to non-invasive approach. Procedia Eng. 2014;87:320–3.

    Article  CAS  Google Scholar 

  101. Zielie PJ, Mobley JA, Ebb RG, Jiang Z, Blute RD, Ho SM. A novel diagnostic test for prostate cancer emerges from the determination of α-methylacyl-coenzyme A racemase in prostatic secretions. J Urol. 2004;172:1130–3.

    Article  CAS  PubMed  Google Scholar 

  102. Rice KR, Chen Y, Ali A, Whitman EJ, Blase A, Ibrahim M, et al. Evaluation of the ETS-related gene mRNA in urine for the detection of prostate cancer. Clin Cancer Res. 2010;16:1572–6.

    Article  CAS  PubMed  Google Scholar 

  103. Talesa VN, Antognelli C, Del Buono C, Stracci F, Serva MR, Cottini E, et al. Diagnostic potential in prostate cancer of a panel of urinary molecular tumor markers. Cancer Biomark: Sect A Dis Markers. 2009;5:241–51.

    Article  CAS  Google Scholar 

  104. Wang F, Ren S, Chen R, Lu J, Shi X, Zhu Y, et al. Development and prospective multicenter evaluation of the long noncoding RNA MALAT-1 as a diagnostic urinary biomarker for prostate cancer. Oncotarget. 2014;5:11091–102.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Rigau M, Morote J, Mir MC, Ballesteros C, Ortega I, Sanchez A, et al. PSGR and PCA3 as biomarkers for the detection of prostate cancer in urine. Prostate. 2010;70:1760–7.

    Article  PubMed  Google Scholar 

  106. Zhu Y, Ren S, Jing T, Cai X, Liu Y, Wang F, et al. Clinical utility of a novel urine-based gene fusion TTTY15-USP9Y in predicting prostate biopsy outcome. Urol Oncol. 2015;33:384.e389–384.e320.

    Article  CAS  Google Scholar 

  107. Rogers CG, Gonzalgo ML, Yan G, Bastian PJ, Chan DY, Nelson WG, et al. High concordance of gene methylation in post-digital rectal examination and post-biopsy urine samples for prostate cancer detection. J Urol. 2006;176:2280–4.

    Article  CAS  PubMed  Google Scholar 

  108. Vener T, Derecho C, Baden J, Wang H, Rajpurohit Y, Skelton J, et al. Development of a multiplexed urine assay for prostate cancer diagnosis. Clin Chem. 2008;54:874–82.

    Article  CAS  PubMed  Google Scholar 

  109. Baden J, Green G, Painter J, Curtin K, Markiewicz J, Jones J, et al. Multicenter evaluation of an investigational prostate cancer methylation assay. J Urol. 2009;182:1186–93.

    Article  CAS  PubMed  Google Scholar 

  110. Baden J, Adams S, Astacio T, Jones J, Markiewicz J, Painter J, et al. Predicting prostate biopsy result in men with prostate specific antigen 2.0 to 10.0 ng/ml using an investigational prostate cancer methylation assay. J Urol. 2011;186:2101–6.

    Article  PubMed  Google Scholar 

  111. Goessl C, Müller M, Heicappell R, Krause H, Straub B, Schrader M, et al. DNA-based detection of prostate cancer in urine after prostatic massage. Urology. 2001;58:335–8.

    Article  CAS  PubMed  Google Scholar 

  112. Cairns P, Esteller M, Herman JG, Schoenberg M, Jeronimo C, Sanchez-Cespedes M, et al. Molecular detection of prostate cancer in urine by GSTP1 hypermethylation. Clin Cancer Res. 2001;7:2727–30.

    CAS  PubMed  Google Scholar 

  113. Jernimo C, Usadel H, Henrique R, Silva C, Oliveira J, Lopes C, et al. Quantitative GSTP1 hypermethylation in bodily fluids of patients with prostate cancer. Urology. 2002;60:1131–5.

    Article  Google Scholar 

  114. Gonzalgo ML, Pavlovich CP, Lee SM, Nelson WG. Prostate cancer detection by GSTP1 methylation analysis of postbiopsy urine specimens. Clin Cancer Res. 2003;9:2673–7.

    CAS  PubMed  Google Scholar 

  115. Minciu R, Dumache R, Gheorghe P, Daminescu L, Rogobete AF, Ionescu D. Molecular diagnostic of prostate cancer from body fluids using methylation-specific PCR (MS-PCR) method. Clin Lab. 2016;62:1183–6.

    CAS  PubMed  Google Scholar 

  116. Woodson K, O’Reilly KJ, Hanson JC, Nelson D, Walk EL, Tangrea JA. The usefulness of the detection of GSTP1 methylation in urine as a biomarker in the diagnosis of prostate cancer. J Urol. 2008;179:508–12.

    Article  CAS  PubMed  Google Scholar 

  117. Payne SR, Serth J, Schostak M, Kamradt J, Strauss A, Thelen P, et al. DNA methylation biomarkers of prostate cancer: confirmation of candidates and evidence urine is the most sensitive body fluid for non-invasive detection. Prostate. 2009;69:1257–69.

    Article  CAS  PubMed  Google Scholar 

  118. Daniunaite K, Jarmalaite S, Kalinauskaite N, Petroska D, Laurinavicius A, Lazutka JR, et al. Prognostic value of RASSF1 promoter methylation in prostate cancer. J Urol. 2014;192:1849–55.

    Article  CAS  PubMed  Google Scholar 

  119. Lombardo ME, Hudson PB. Preliminary evaluation of 5α-reductase type 2 in urine as a potential marker for prostate disease. Steroids. 1997;62:682–5.

    Article  CAS  PubMed  Google Scholar 

  120. Overbye A, Skotland T, Koehler CJ, Thiede B, Seierstad T, Berge V, et al. Identification of prostate cancer biomarkers in urinary exosomes. Oncotarget. 2015;6:30357–76.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Schostak M, Schwall GP, Poznanovic S, Groebe K, Muller M, Messinger D, et al. Annexin A3 in urine: a highly specific noninvasive marker for prostate cancer early detection. J Urol. 2009;181:343–53.

    Article  CAS  PubMed  Google Scholar 

  122. Jedinak A, Curatolo A, Zurakowski D, Dillon S, Bhasin MK, Libermann TA, et al. Novel non-invasive biomarkers that distinguish between benign prostate hyperplasia and prostate cancer. BMC Cancer. 2015;15:259.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Sánchez-Carbayo M, Urrutia M, de Buitrago JMG, Navajo JA. Evaluation of two new urinary tumor markers: bladder tumor fibronectin and cytokeratin 18 for the diagnosis of bladder cancer. Clin Cancer Res. 2000;6:3585–94.

    PubMed  Google Scholar 

  124. Tanaka M, Tanaka T, Matsuzaki S, Seto Y, Matsuda T, Komori K, et al. Rapid and quantitative detection of human septin family Bradeion as a practical diagnostic method of colorectal and urologic cancers. Med Sci Monit. 2003;9:Mt61–68.

    CAS  PubMed  Google Scholar 

  125. Russo AL, Jedlicka K, Wernick M, McNally D, Kirk M, Sproull M, et al. Urine analysis and protein networking identify met as a marker of metastatic prostate cancer. Clin Cancer Res. 2009;15:4292–8.

    Article  CAS  PubMed  Google Scholar 

  126. Zhang M, Chen L, Yuan Z, Yang Z, Li Y, Shan L, et al. Combined serum and EPS-urine proteomic analysis using iTRAQ technology for discovery of potential prostate cancer biomarkers. Discov Med. 2016;22:281–95.

    PubMed  Google Scholar 

  127. Lu Q, Zhang J, Allison R, Gay H, Yang W-X, Bhowmick NA, et al. Identification of extracellular δ-catenin accumulation for prostate cancer detection. Prostate. 2008;69:411–8.

    Article  CAS  Google Scholar 

  128. Fujita K, Ewing CM, Chan DY, Mangold LA, Partin AW, Isaacs WB, et al. Endoglin (CD105) as a urinary and serum marker of prostate cancer. Int J Cancer. 2009;124:664–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Morgan R, Boxall A, Bhatt A, Bailey M, Hindley R, Langley S, et al. Engrailed-2 (EN2): a tumor specific urinary biomarker for the early diagnosis of prostate cancer. Clin Cancer Res. 2011;17:1090–8.

    Article  CAS  PubMed  Google Scholar 

  130. Pandha H, Sorensen KD, Orntoft TF, Langley S, Hoyer S, Borre M, et al. Urinary engrailed-2 (EN2) levels predict tumour volume in men undergoing radical prostatectomy for prostate cancer. BJU Int. 2012;110:E287–E292.

    Article  CAS  PubMed  Google Scholar 

  131. Killick E, Morgan R, Launchbury F, Bancroft E, Page E, Castro E, et al. Role of engrailed-2 (EN2) as a prostate cancer detection biomarker in genetically high risk men. Sci Rep. 2013;3:2059.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Haj-Ahmad TA, Abdalla MAK, Haj-Ahmad Y. Potential urinary protein biomarker candidates for the accurate detection of prostate cancer among benign prostatic hyperplasia patients. J Cancer. 2014;5:103–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kojima Y, Yoneyama T, Hatakeyama S, Mikami J, Sato T, Mori K, et al. Detection of Core2 β-1,6-N-acetylglucosaminyltransferase in post-digital rectal examination urine is a reliable indicator for extracapsular extension of prostate cancer. PLoS ONE. 2015;10:e0138520.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Fujita K, Ewing CM, Isaacs WB, Pavlovich CP. Immunomodulatory IL-18 binding protein is produced by prostate cancer cells and its levels in urine and serum correlate with tumor status. Int J Cancer. 2011;129:424–32.

    Article  CAS  PubMed  Google Scholar 

  135. Stoeber K, Swinn R, Prevost AT, de Clive-Lowe P, Halsall I, Dilworth SM, et al. Diagnosis of genito-urinary tract cancer by detection of minichromosome maintenance 5 protein in urine sediments. J Natl Cancer Inst. 2002;94:1071–9.

    Article  CAS  PubMed  Google Scholar 

  136. Roy R, Louis G, Loughlin KR, Wiederschain D, Kilroy SM, Lamb CC, et al. Tumor-specific urinary matrix metalloproteinase fingerprinting: identification of high molecular weight urinary matrix metalloproteinase species. Clin Cancer Res. 2008;14:6610–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Rehman I, Azzouzi AR, Catto JWF, Allen S, Cross SS, Feeley K, et al. Proteomic analysis of voided urine after prostatic massage from patients with prostate cancer: a pilot study. Urology. 2004;64:1238–43.

    Article  CAS  PubMed  Google Scholar 

  138. Müller H, Haug U, Rothenbacher D, Stegmaier C, Brenner H. Evaluation of serum and urinary myeloid related protein-14 as a marker for early detection of prostate cancer. J Urol. 2008;180:1309–13.

    Article  PubMed  Google Scholar 

  139. Flatley B, Wilmott KG, Malone P, Cramer R. MALDI MS profiling of post-DRE urine samples highlights the potential of β-microseminoprotein as a marker for prostatic diseases. Prostate. 2013;74:103–11.

    Article  PubMed  CAS  Google Scholar 

  140. Bolduc S, Lacombe L, Naud A, Gregoire M, Fradet Y, Tremblay RR. Urinary PSA: a potential useful marker when serum PSA is between 2.5 ng/mL and 10 ng/mL. Can Urol Assoc J. 2007;1:377–81.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Iwakiri J, Grandbois K, Wehner N, Graves HCB, Stamey T. An analysis of urinary prostate specific antigen before and after radical prostatectomy: evidence for secretion of prostate specific antigen by the periurethral glands. J Urol. 1993;149:783–6.

    Article  CAS  PubMed  Google Scholar 

  142. Tremblay J, Frenette G, Tremblay RR, Dupont A, Thabet M, Dube JY. Excretion of three major prostatic secretory proteins in the urine of normal men and patients with benign prostatic hypertrophy or prostate cancer. Prostate. 1987;10:235–43.

    Article  CAS  PubMed  Google Scholar 

  143. Fujita K, Hayashi T, Matsuzaki K, Nakata W, Masuda M, Kawashima A, et al. Decreased fucosylated PSA as a urinary marker for high Gleason score prostate cancer. Oncotarget. 2016;7:56643–9.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Nakayama K, Inoue T, Sekiya S, Terada N, Miyazaki Y, Goto T, et al. The C-Terminal fragment of prostate-specific antigen, a 2331 da peptide, as a new urinary pathognomonic biomarker candidate for diagnosing prostate cancer. PLoS ONE. 2014;9:e107234.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Drake RR, White KY, Fuller TW, Igwe E, Clements MA, Nyalwidhe JO, et al. Clinical collection and protein properties of expressed prostatic secretions as a source for biomarkers of prostatic disease. J Proteom. 2009;72:907–17.

    Article  CAS  Google Scholar 

  146. Mitchell PJ, Welton J, Staffurth J, Court J, Mason MD, Tabi Z, et al. Can urinary exosomes act as treatment response markers in prostate cancer?. J Transl Med. 2009;7:4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Teni TR, Sheth AR, Kamath MR, Sheth NA. Serum and urinary prostatic inhibin-like peptide in benign prostatic hyperplasia and carcinoma of prostate. Cancer Lett. 1988;43:9–14.

    Article  CAS  PubMed  Google Scholar 

  148. Teni TR, Bandivdekar AH, Sheth AR, Sheth NA. Prostatic inhibin-like peptide quantified in urine of prostatic cancer patients by enzyme-linked immunosorbent assay. Clin Chem. 1989;35:1376.

    Article  CAS  PubMed  Google Scholar 

  149. Rosen EM, Joseph A, Jin L, Yao Y, Chau M-HT, Fuchs A, et al. Urinary and tissue levels of scatter factor in transitional cell carcinoma of bladder. J Urol. 1997;157:72–78.

    Article  CAS  PubMed  Google Scholar 

  150. Smith SD, Wheeler MA, Plescia J, Colberg JW, Weiss RM, Altieri DC. Urine detection of survivin and diagnosis of bladder cancer. JAMA. 2001;285:324–8.

    Article  CAS  PubMed  Google Scholar 

  151. Adamson AS, Francis JL, Witherow RON, Snell ME. Urinary tissue factor levels in prostatic carcinoma: a potential. marker of metastatic spread?. Br J Urol. 1993;71:587–92.

    Article  CAS  PubMed  Google Scholar 

  152. Lwaleed BA, Francis JL, Chisholm M. Urinary tissue factor levels in patients with bladder and prostate cancer. Eur J Surg Oncol. 2000;26:44–49.

    Article  CAS  PubMed  Google Scholar 

  153. Fernandez C, Rifai N, Wenger AS, Mickey DD, Silverman LM. A preliminary study of urinary transferrin as a marker for prostatic cancer. Clin Chim Acta. 1986;161:335–9.

    Article  CAS  PubMed  Google Scholar 

  154. van Dieijen-Visser MP, Hendriks MW, Delaere KP, Gijzen AH, Brombacher PJ. The diagnostic value of urinary transferrin compared to serum prostatic specific antigen (PSA) and prostatic acid phosphatase (PAP) in patients with prostatic cancer. Clin Chim Acta. 1988;177:77–80.

    Article  PubMed  Google Scholar 

  155. Hutchinson LM, Chang EL, Becker CM, Shih M-C, Brice M, DeWolf WC, et al. Use of thymosin β15 as a urinary biomarker in human prostate cancer. Prostate. 2005;64:116–27.

    Article  CAS  PubMed  Google Scholar 

  156. Katafigiotis I, Tyritzis SI, Stravodimos KG, Alamanis C, Pavlakis K, Vlahou A, et al. Zinc alpha2-glycoprotein as a potential novel urine biomarker for the early diagnosis of prostate cancer. BJU Int. 2012;110:E688–693.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge funding support from the Prostate Cancer Foundation, Urological Research Foundation, and NIH grants U54CA199091, P50CA180995, and X01HG009642 to WJC.

Author information

Authors and Affiliations

  1. Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Jillian N. Eskra, Daniel Rabizadeh, Christian P. Pavlovich & Jun Luo

  2. Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    William J. Catalona

Authors
  1. Jillian N. Eskra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel Rabizadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christian P. Pavlovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William J. Catalona
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jun Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jun Luo.

Ethics declarations

Conflict of interest

WJC is a consultant/advisory board member for Beckman Coulter and has received commercial research support from Beckman Coulter, DeCode Genetics, and Ohmx. JL, CPP, JNE, and DR declare no conflict of interest.

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Eskra, J.N., Rabizadeh, D., Pavlovich, C.P. et al. Approaches to urinary detection of prostate cancer. Prostate Cancer Prostatic Dis 22, 362–381 (2019). https://doi.org/10.1038/s41391-019-0127-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41391-019-0127-4

This article is cited by

Search

Advanced search

Quick links