Potential Epigenetic Biomarkers for Prostate Cancer Screening

Article information

Int Neurourol J. 2018;22(2):142-144
Publication date (electronic) : 2018 June 30
doi : https://doi.org/10.5213/inj.1836096.048
Department of Preventive Medicine, Jeju National University School of Medicine, Jeju, Korea
Corresponding author: Jong-Myon Bae https://orcid.org/0000-0003-3080-7852 Department of Preventive Medicine, Jeju National University School of Medicine, 102 Jejudaehak-ro, Jeju 63243, Korea E-mail: jmbae@jejunu.ac.kr / Tel: +82-64-755-5567 / Fax: +82-64-758-3231
Received 2018 April 11; Accepted 2018 May 24.

To the editor:

Chiam et al. [1] stated that prostate cancer (PCa) is a major global health problem that imposes a significant economic burden in nations with an aging population. The annual percentage change (APC) of the incidence of PCa in Korean men was 13.7% from 1999 to 2009, and APC of mortality rates was 17.5% from 1999 to 2002 [2]. The widespread use of prostate-specific antigen (PSA)-based screening testing (PSA-ST) leads to an increased incidence of PCa because it enables the earlier detection of occult or asymptomatic disease [3-5].

As PSA is not a specific marker of PCa [1], recommendations on PSA-ST for PCa vary in terms of the screening age and interval [6,7]. Of note, the 2012 U.S. Preventive Services Task Force guideline [8] recommended against routine screening for PCa, because the benefits of PSA-ST for PCa do not outweigh the harms.

The harms of PSA-ST can be summarized as overdiagnosis, unnecessary biopsies with potential associated adverse effects, anxiety, and excessive treatment [7,9,10]. As such, the most serious limitation of PSA-ST as a screening modality is the fact that PSA levels can be elevated in patients with benign prostatic hyperplasia or prostatitis, as well as in PCa patients [7,11]. This phenomenon may give rise to overdiagnosis, resulting in overtreatment [1,6,12,13]. In addition to this, PSA-ST has very poor sensitivity, specificity, and predictive values because there are no absolute cutoff PSA levels defining PCa [1,13]. Thus, Lee et al. [14] concluded that PSA-ST alone did not increase earlystage PCa detection or reduce mortality.

To overcome these limitations of PSA-ST, PSA velocity [15], testing for 4 prostate-specific kallikreins [3], the prostate health index test [16], the percentage of free PSA [17], and tests for noncoding prostate-tissue-specific RNA [18] have been introduced. However, these PSA derivatives may be impractical or only helpful in specific situations [1,7]. Thus, novel biomarkers capable of replacing serum PSA for PCa screening must be investigated [19-22]. In addition, reliable and accurate biomarkers for discriminating between indolent and aggressive tumors at the early stage of PCa are needed [23].

As age, race, and environment are known to be the main risk factors for PCa, epigenetic studies investigating the carcinogenesis of PCa through gene-environment interactions have been conducted [1,24]. Current evidence suggests that epigenetic alterations of aberrant DNA methylation, histone modifications, and noncoding microRNA are associated with the carcinogenesis of PCa [25-28]. Thus, potential biomarkers related to a high frequency of epigenetic changes may improve the sensitivity and specificity of the diagnosis (including early detection) and prognosis of PCa [1,13,25,27,29].

Chiam et al. [1] tabulated the epigenetic biomarkers associated with the diagnosis, prognosis, and treatment response of PCa. Furthermore, Yegnasubramanian [13] suggested that methylation in the regulatory regions of GSTP1, APC, PTGS2, RARB, and RASSF1A may be epigenetic biomarkers for PCa screening. In particular, measurements of GSTP1 promoter methylation in plasma, serum, whole blood, urine, ejaculate, or prostatic secretions may complement PSA-ST for PCa based on a meta-analysis of 22 studies [30]. However, all those studies were case-control studies with a small sample size. Thus, a population-based cohort study in asymptomatic men with a large sample size is needed to evaluate the effectiveness of GSTP1 for the early detection of PCa and/or the identification of aggressive tumors.

In conclusion, the controversies regarding PSA-ST have led to the need for a more accurate biomarker suitable for the early detection of PCa [31]. This unmet need could be satisfied by epigenetic biomarkers related to the pathogenesis of PCa [13,29].

However, potential epigenetic markers require further research to be validated for screening in diverse populations [25,32]. Further studies may lead to the development of epigenetic markers that could replace, rather than complement, PSA-ST due to advantages in sensitivity.


Conflict of Interest

No potential conflict of interest relevant to this article was reported.


1. Chiam K, Ricciardelli C, Bianco-Miotto T. Epigenetic biomarkers in prostate cancer: Current and future uses. Cancer Lett 2014;342:248–56.
2. Jung KW, Won YJ, Kong HJ, Lee ES, ; Community of PopulationBased Regional Cancer Registries. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2015. Cancer Res Treat 2018;50:303–16.
3. Eastham J. Prostate cancer screening. Investig Clin Urol 2017;58:217–9.
4. Welch HG, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst 2010;102:605–13.
5. Bae JM. Epidemiological evidences on overdiagnosis of prostate and kidney cancers in Korean. Epidemiol Health 2015;37:e2015015.
6. Pinsky PF, Prorok PC, Kramer BS. Prostate cancer screening - a perspective on the current state of the evidence. N Engl J Med 2017;376:1285–9.
7. Stewart RW, Lizama S, Peairs K, Sateia HF, Choi Y. Screening for prostate cancer. Semin Oncol 2017;44:47–56.
8. Moyer VA, ; U.S. Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012;157:120–34.
9. Loeb S. Evidence-based versus personalized prostate cancer screening: using baseline prostate-specific antigen measurements to individualize screening. J Clin Oncol 2016;34:2684–6.
10. Ruane-McAteer E, Porter S, O’Sullivan JM, Santin O, Prue G. Active surveillance for favorable-risk prostate cancer: Is there a greater psychological impact than previously thought? A systematic, mixed studies literature review. Psychooncology 2017;26:1411–21.
11. Roehrborn CG, Boyle P, Gould AL, Waldstreicher J. Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. Urology 1999;53:581–9.
12. Mundbjerg K, Chopra S, Alemozaffar M, Duymich C, Lakshminarasimhan R, Nichols PW, et al. Identifying aggressive prostate cancer foci using a DNA methylation classifier. Genome Biol 2017;18:3.
13. Yegnasubramanian S. Prostate cancer epigenetics and its clinical implications. Asian J Androl 2016;18:549–58.
14. Lee YJ, Park JE, Jeon BR, Lee SM, Kim SY, Lee YK. Is prostate-specific antigen effective for population screening of prostate cancer? A systematic review. Ann Lab Med 2013;33:233–41.
15. Lee HW, Kwak KW, Choi YH, Choi HY, Lee HM. New thresholds for prostate-specific antigen velocity for prostate cancer screening in Korean patients younger than 60 years old. Korean J Urol 2008;49:113–7.
16. Catalona WJ, Partin AW, Sanda MG, Wei JT, Klee GG, Bangma CH, et al. A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/mL prostate specific antigen range. J Urol 2011;185:1650–5.
17. Lee R, Localio AR, Armstrong K, Malkowicz SB, Schwartz JS, ; Free PSA Study Group. A meta-analysis of the performance characteristics of the free prostate-specific antigen test. Urology 2006;67:762–8.
18. 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.
19. Endzeliņš E, Melne V, Kalniņa Z, Lietuvietis V, Riekstiņa U, Llorente A, et al. Diagnostic, prognostic and predictive value of cell-free miRNAs in prostate cancer: a systematic review. Mol Cancer 2016;15:41.
20. Shariat SF, Semjonow A, Lilja H, Savage C, Vickers AJ, Bjartell A. Tumor markers in prostate cancer I: blood-based markers. Acta Oncol 2011;50 Suppl 1:61–75.
21. Bjartell A, Montironi R, Berney DM, Egevad L. Tumour markers in prostate cancer II: diagnostic and prognostic cellular biomarkers. Acta Oncol 2011;50 Suppl 1:76–84.
22. Roobol MJ, Haese A, Bjartell A. Tumour markers in prostate cancer III: biomarkers in urine. Acta Oncol 2011;50 Suppl 1:85–9.
23. Dmitriev AA, Rosenberg EE, Krasnov GS, Gerashchenko GV, Gordiyuk VV, Pavlova TV, et al. Identification of novel epigenetic markers of prostate cancer by NotI-Microarray analysis. Dis Markers 2015;2015:241301.
24. Chinaranagari S, Sharma P, Bowen NJ, Chaudhary J. Prostate cancer epigenome. Methods Mol Biol 2015;1238:125–40.
25. Jerónimo C, Bastian PJ, Bjartell A, Carbone GM, Catto JW, Clark SJ, et al. Epigenetics in prostate cancer: biologic and clinical relevance. Eur Urol 2011;60:753–66.
26. Kgatle MM, Kalla AA, Islam MM, Sathekge M, Moorad R. Prostate cancer: epigenetic alterations, risk factors, and therapy. Prostate Cancer 2016;2016:5653862.
27. Yang M, Park JY. DNA methylation in promoter region as biomarkers in prostate cancer. Methods Mol Biol 2012;863:67–109.
28. Geybels MS, Zhao S, Wong CJ, Bibikova M, Klotzle B, Wu M, et al. Epigenomic profiling of DNA methylation in paired prostate cancer versus adjacent benign tissue. Prostate 2015;75:1941–50.
29. Blute ML Jr, Damaschke NA, Jarrard DF. The epigenetics of prostate cancer diagnosis and prognosis: update on clinical applications. Curr Opin Urol 2015;25:83–8.
30. Wu T, Giovannucci E, Welge J, Mallick P, Tang WY, Ho SM. Measurement of GSTP1 promoter methylation in body fluids may complement PSA screening: a meta-analysis. Br J Cancer 2011;105:65–73.
31. Troyer DA, Mubiru J, Leach RJ, Naylor SL. Promise and challenge: markers of prostate cancer detection, diagnosis and prognosis. Dis Markers 2004;20:117–28.
32. Wu Y, Sarkissyan M, Vadgama JV. Epigenetics in breast and prostate cancer. Methods Mol Biol 2015;1238:425–66.

Article information Continued