Introduction. Predicting the aggressiveness of prostate cancer at biopsy is invaluable in making treatment decisions. In this paper we review the differential expression of genes and microRNAs identified through microarray analysis as potentially useful markers for prostate cancer prognosis and discuss some of the challenges associated with their development. Methods. A review of the literature was conducted through Medline. Articles were identified through searches of the following terms: “prostate cancer AND differential expression”, “prostate cancer prognosis”, and “prostate cancer AND microRNAs”. Results. Though numerous differentially expressed genes and microRNAs were identified as possible prognostic markers, the significance of several of these genes is either debated due to conflicting results or is not validated in other study populations. A few of the articles constructed predictive nomograms using a panel of biomarkers which require further validation. Challenges to the development of useful markers include different methodology, cancer heterogeneity, and sampling error. These can be overcome by categorizing prognostic factors into particular gene pathways or by supplementing biopsy information with blood or urine-based biomarkers. Conclusion. Though biomarkers based on differential expression offer the potential to improve decision making concerning prostate cancer, further validation of their utility and accuracy at the biopsy level is needed. 1. Introduction Prostate cancer is estimated to be diagnosed in 241,740 men in the USA in 2012 [1]. For men in developed countries, it represents the most common cancer diagnosed in men and the second most common cause of cancer-specific mortality [2]. In approximately 90% of those men who are diagnosed, prostate cancer is in a localized, potentially curable state [3]. Since PSA screening has been introduced, the mortality rate of prostate cancer has decreased in part due to improved treatment [4]. However, as evidenced by a few large randomized trials of PSA screening, prostate cancer is overtreated in many instances, subjecting patients to the morbidity of treatment [5, 6]. In an attempt to reduce treatment morbidity in patients who otherwise have indolent cancer, clinicians have developed protocols for active surveillance by which low-risk patients can be monitored for progression. However, through limitations in prostate biopsy resulting in sampling error, as many as 33% are reclassified, with the majority of these occurring on the first repeat biopsy [7]. By itself Gleason score offers the best
References
[1]
R. Siegel, E. Ward, O. Brawley, and A. Jemal, “Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths,” CA Cancer Journal for Clinicians, vol. 61, no. 4, pp. 212–236, 2011.
[2]
A. Jemal, F. Bray, M. M. Center, J. Ferlay, E. Ward, and D. Forman, “Global cancer statistics,” CA Cancer Journal for Clinicians, vol. 61, no. 2, pp. 69–90, 2011.
[3]
Y. H. Shao, K. Demissie, W. Shih et al., “Contemporary risk profile of prostate cancer in the United States,” Journal of the National Cancer Institute, vol. 101, no. 18, pp. 1280–1283, 2009.
[4]
K. McDavid, J. Lee, J. P. Fulton, J. Tonita, and T. D. Thompson, “Prostate cancer incidence and mortality rates and trends in the United States and Canada,” Public Health Reports, vol. 119, no. 2, pp. 174–186, 2004.
[5]
G. L. Andriole, E. D. Crawford, R. L. Grubb 3rd et al., “Mortality results from a randomized prostate-cancer screening trial,” New England Journal of Medicine, vol. 360, no. 13, pp. 1310–1319, 2009.
[6]
F. H. Schr？der, J. Hugosson, M. J. Roobol et al., “Screening and prostate-cancer mortality in a randomized european study,” New England Journal of Medicine, vol. 360, no. 13, pp. 1320–1328, 2009.
[7]
J. I. Epstein, Z. Feng, B. J. Trock, and P. M. Pierorazio, “Upgrading and downgrading of prostate cancer from biopsy to radical prostatectomy: incidence and predictive factors using the modified Gleason grading system and factoring in tertiary grades,” European Journal of Urology, vol. 61, no. 5, pp. 1019–1024, 2012.
[8]
A. J. Stephenson, P. T. Scardino, J. A. Eastham et al., “Preoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy,” Journal of the National Cancer Institute, vol. 98, no. 10, pp. 715–717, 2006.
[9]
M. R. Cooperberg, D. J. Pasta, E. P. Elkin et al., “The University of California, San Francisco Cancer of the Prostate Risk Assessment score: a straightforward and reliable preoperative predictor of disease recurrence after radical prostatectomy,” Journal of Urology, vol. 173, no. 6, pp. 1938–1942, 2005.
[10]
A. J. Stephenson, P. T. Scardino, M. W. Kattan et al., “Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy,” Journal of Clinical Oncology, vol. 25, no. 15, pp. 2035–2041, 2007.
[11]
T. L. Lotan, B. Gurel, S. Sutcliffe et al., “PTEN protein loss by immunostaining: analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients,” Clinical Cancer Research, vol. 17, no. 20, pp. 6563–6573, 2011.
[12]
S. Jhavar, D. Brewer, S. Edwards et al., “Integration of ERG gene mapping and gene-expression profiling identifies distinct categories of human prostate cancer,” British Journal of Urology International, vol. 103, no. 9, pp. 1256–1269, 2009.
[13]
S. Jhavar, D. Brewer, S. Edwards et al., “Integration of ERG gene mapping and gene-expression profiling identifies distinct categories of human prostate cancer,” British Journal of Urology International, vol. 103, no. 9, pp. 1256–1269, 2009.
[14]
C. M. Koh, C. J. Bieberich, C. V. Dang, W. G. Nelson, S. Yegnasubramanian, and A. M. De Marzo, “MYC and prostate cancer,” Genes and Cancer, vol. 1, no. 6, pp. 617–628, 2010.
[15]
C. Schroten, N. F. Dits, E. W. Steyerberg et al., “The additional value of TGFβ1 and IL-7 to predict the course of prostate cancer progression,” Cancer Immunology, Immunotherapy, vol. 61, no. 6, pp. 905–910, 2012.
[16]
E. V. Vykhovanets, S. Shukla, G. T. MacLennan et al., “Molecular imaging of NF-kappaB in prostate tissue after systemic administration of IL-1β,” Prostate, vol. 68, no. 1, pp. 34–41, 2008.
[17]
A. Azevedo, V. Cunha, and A. L. Teixeira, “IL-6/IL-6R as a potential key signaling pathway in prostate cancer development,” World Journal of Clinical Oncology, vol. 2, no. 12, pp. 384–396, 2011.
[18]
T. Sun, G. S. M. Lee, W. K. Oh et al., “Inherited variants in the chemokine CCL2 gene and prostate cancer aggressiveness in a caucasian cohort,” Clinical Cancer Research, vol. 17, no. 6, pp. 1546–1552, 2011.
[19]
A. J. Liu, B. Furusato, L. Ravindranath et al., “Quantitative analysis of a panel of gene expression in prostate cancer—with emphasis on NPY expression analysis,” Journal of Zhejiang University. Science. B, vol. 8, no. 12, pp. 853–859, 2007.
[20]
Z. Ding, C. J. Wu, G. C. Chu et al., “SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression,” Nature, vol. 470, no. 7333, pp. 269–276, 2011.
[21]
S. H. Madani, S. Ameli, S. Khazaei, M. Kanani, and B. Izadi, “Frequency of Ki-67 (MIB-1) and P53 expressions among patients with prostate cancer,” Indian Journal of Pathology and Microbiology, vol. 54, no. 4, pp. 688–691, 2011.
[22]
B. Verdoodt, F. Sommerer, R.-J. Palisaar et al., “Inverse association of and methylation of the CDKN2a locus in different Gleason scores of prostate cancer,” Prostate Cancer and Prostatic Diseases, vol. 14, no. 4, pp. 295–301, 2011.
[23]
S. Aaltomaa, P. Lipponen, M. Eskelinen, M. Ala-Opas, and V. M. Kosma, “Prognostic value and expression of p21(wafl/cip I) protein in prostate cancer,” Prostate, vol. 39, no. 1, pp. 8–15, 1999.
[24]
J. J. Bauer, I. A. Sesterhenn, F. K. Mostofi, D. G. Mcleod, S. Srivastava, and J. W. Moul, “Elevated levels of apoptosis regulator proteins p53 and bcl-2 are independent prognostic biomarkers in surgically treated clinically localized prostate cancer,” Journal of Urology, vol. 156, no. 4, pp. 1511–1516, 1996.
[25]
D. S. Scherr, E. D. Vaughan, J. Wei et al., “bcl-2 and p53 expression in clinically localized prostate cancer predicts response to external beam radiotherapy,” Journal of Urology, vol. 162, no. 1, pp. 12–17, 1999.
[26]
L. Y. Khor, J. Moughan, T. Al-Saleem et al., “Bcl-2 and bax expression predict prostate cancer outcome in men treated with androgen deprivation and radiotherapy on radiation therapy oncology group protocol 92-02,” Clinical Cancer Research, vol. 13, no. 12, pp. 3585–3590, 2007.
[27]
M. Peyromaure, C. Badoual, P. Camparo et al., “Plasma levels and expression of vascular endothelial growth factor-A in human localized prostate cancer,” Oncology Reports, vol. 18, no. 1, pp. 145–149, 2007.
[28]
R. Mori, T. B. Dorff, S. Xiong et al., “The relationship between proangiogenic gene expression levels in prostate cancer and their prognostic value for clinical outcomes,” Prostate, vol. 70, no. 15, pp. 1692–1700, 2010.
[29]
A. Drivalos, A. G. Papatsoris, M. Chrisofos, E. Efstathiou, and M. A. Dimopoulos, “The role of the cell adhesion molecules (integrins/cadherins) in prostate cancer,” International Brazilian Journal of Urology, vol. 37, no. 3, pp. 302–306, 2011.
[30]
Y. J. Shin and J.-H. Kim, “The role of EZH2 in the regulation of the activity of matrix metalloproteinases in prostate cancer cells,” PLoS ONE, vol. 7, no. 1, Article ID e30393, 2012.
[31]
J. Li, Q. H. Fan, X. S. Fan, W. Zhou, Y. Qiu, and L. Qiu, “EZH2 expression in human prostate cancer and its clinicopathologic significance,” National Journal of Andrology, vol. 16, no. 2, pp. 123–128, 2010.
[32]
M. Anees, P. Horak, A. El-Gazzar et al., “Recurrence-free survival in prostate cancer is related to increased stromal TRAIL expression,” Cancer, vol. 117, no. 6, pp. 1172–1182, 2011.
[33]
P. Vainio, L. Lehtinen, T. Mirtti et al., “Phospholipase PLA2G7, associated with aggressive prostate cancer, promotes prostate cancer cell migration and invasion and is inhibited by statins,” Oncotarget, vol. 2, no. 12, pp. 1176–1190, 2011.
[34]
P. Vainio, S. Gupta, K. Ketola et al., “Arachidonic acid pathway members PLA2G7, HPGD, EPHX2, and CYP4F8 identified as putative novel therapeutic targets in prostate cancer,” American Journal of Pathology, vol. 178, no. 2, pp. 525–536, 2011.
[35]
I. A. Voutsadakis, P. J. Vlachostergios, D. D. Daliani et al., “CD10 is inversely associated with nuclear factor-kappa B and predicts biochemical recurrence after radical prostatectomy,” Urologia Internationalis, vol. 88, no. 2, pp. 158–164, 2012.
[36]
G. C. Blobe, W. P. Schiemann, and H. F. Lodish, “Role of transforming growth factor β in human disease,” New England Journal of Medicine, vol. 342, no. 18, pp. 1350–1358, 2000.
[37]
E. Di Carlo, T. D'Antuono, P. Pompa et al., “The lack of epithelial interleukin-7 and BAFF/BLyS gene expression in prostate cancer as a possible mechanism of tumor escape from immunosurveillance,” Clinical Cancer Research, vol. 15, no. 9, pp. 2979–2987, 2009.
[38]
J. C. Cheville, R. J. Karnes, T. M. Therneau et al., “Gene panel model predictive of outcome in men at high-risk of systemic progression and death from prostate cancer after radical retropubic prostatectomy,” Journal of Clinical Oncology, vol. 26, no. 24, pp. 3930–3936, 2008.
[39]
M. Bibikova, E. Chudin, A. Arsanjani et al., “Expression signatures that correlated with Gleason score and relapse in prostate cancer,” Genomics, vol. 89, no. 6, pp. 666–672, 2007.
[40]
E. K. Markert, H. Mizuno, A. Vazquez, and A. J. Levine, “Molecular classification of prostate cancer using curated expression signatures,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 52, pp. 21276–21281, 2011.
[41]
G. A. Calin, C. D. Dumitru, M. Shimizu et al., “Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 24, pp. 15524–15529, 2002.
[42]
C. L. Bartels and G. J. Tsongalis, “Mini-reviews micrornas:novel biomarkers for human cancer,” Clinical Chemistry, vol. 55, no. 4, pp. 623–631, 2009.
[43]
A. Gordanpour, R. K. Nam, and L. Sugar, “MicroRNAs in prostate cancer: from biomarkers to molecularly-based therapeutics,” Prostate Cancer and Prostatic Diseases. In press.
[44]
Y. Xi, G. Nakajima, E. Gavin et al., “Systematic analysis of microRNA expression of RNA extracted from fresh frozen and formalin-fixed paraffin-embedded samples,” RNA, vol. 13, no. 10, pp. 1668–1674, 2007.
[45]
M. D. Mattie, C. C. Benz, J. Bowers et al., “Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies,” Molecular Cancer, vol. 5, article 24, 2006.
[46]
L. Nonn, A. Vaishnav, L. Gallagher, and P. H. Gann, “mRNA and micro-RNA expression analysis in laser-capture microdissected prostate biopsies: valuable tool for risk assessment and prevention trials,” Experimental and Molecular Pathology, vol. 88, no. 1, pp. 45–51, 2010.
[47]
K. R. Leite, A. Tomiyama, and S. T. Reis, “MicroRNA expression profiles in the progression of prostate cancer-from high-grade prostate intraepithelial neoplasia to metastasis,” Urologic Oncology. In press.
[48]
D. Bonci, V. Coppola, M. Musumeci et al., “The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities,” Nature Medicine, vol. 14, no. 11, pp. 1271–1277, 2008.
[49]
M. Musumeci, V. Coppola, A. Addario et al., “Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer,” Oncogene, vol. 30, no. 41, pp. 4231–4242, 2011.
[50]
T. Li, D. Li, J. Sha, P. Sun, and Y. Huang, “MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells,” Biochemical and Biophysical Research Communications, vol. 383, no. 3, pp. 280–285, 2009.
[51]
T. Li, R.-S. Li, Y.-H. Li et al., “MiR-21 as an independent biochemical recurrence predictor and potential therapeutic target for prostate cancer,” Journal of Urology, vol. 187, no. 4, pp. 1466–1472, 2012.
[52]
S. Volinia, G. A. Calin, C.-G. Liu et al., “A microRNA expression signature of human solid tumors defines cancer gene targets,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 7, pp. 2257–2261, 2006.
[53]
K. P. Porkka, M. J. Pfeiffer, K. K. Waltering, R. L. Vessella, T. L. J. Tammela, and T. Visakorpi, “MicroRNA expression profiling in prostate cancer,” Cancer Research, vol. 67, no. 13, pp. 6130–6135, 2007.
[54]
S. Ambs, R. L. Prueitt, M. Yi et al., “Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer,” Cancer Research, vol. 68, no. 15, pp. 6162–6170, 2008.
[55]
A. Schaefer, M. Jung, H. J. Mollenkopf et al., “Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma,” International Journal of Cancer, vol. 126, no. 5, pp. 1166–1176, 2010.
[56]
O. W. Rokhlin, V. S. Scheinker, A. F. Taghiyev, D. Bumcrot, R. A. Glover, and M. B. Cohen, “MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate cancer,” Cancer Biology and Therapy, vol. 7, no. 8, pp. 1288–1296, 2008.
[57]
C. Liu, K. Kelnar, B. Liu et al., “The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44,” Nature Medicine, vol. 17, no. 2, pp. 211–216, 2011.
[58]
K. R. M. Leite, A. Tomiyama, S. T. Reis et al., “MicroRNA-100 expression is independently related to biochemical recurrence of prostate cancer,” Journal of Urology, vol. 185, no. 3, pp. 1118–1122, 2011.
[59]
A. W. Tong, P. Fulgham, C. Jay et al., “MicroRNA profile analysis of human prostate cancers,” Cancer Gene Therapy, vol. 16, no. 3, pp. 206–216, 2009.
[60]
J. Shen, G. W. Hruby, J. M. McKiernan, et al., “Dysregulation of circulating microRNAs and prediction of aggressive prostate cancer,” Prostate, vol. 72, no. 13, pp. 1469–1477, 2012.
[61]
M. Sachdeva, S. Zhu, F. Wu et al., “p53 represses c-Myc through induction of the tumor suppressor miR-145,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 9, pp. 3207–3212, 2009.
[62]
L. Wang, H. Tang, V. Thayanithy et al., “Gene networks and microRNAs implicated in aggressive prostate cancer,” Cancer Research, vol. 69, no. 24, pp. 9490–9497, 2009.
[63]
W. Gao, H. Shen, L. Liu, J. Xu, J. Xu, and Y. Shu, “MiR-21 overexpression in human primary squamous cell lung carcinoma is associated with poor patient prognosis,” Journal of Cancer Research and Clinical Oncology, vol. 137, no. 4, pp. 557–566, 2011.
[64]
M. V. Iorio, M. Ferracin, C. G. Liu et al., “MicroRNA gene expression deregulation in human breast cancer,” Cancer Research, vol. 65, no. 16, pp. 7065–7070, 2005.
[65]
T. Schepeler, J. T. Reinert, M. S. Ostenfeld et al., “Diagnostic and prognostic microRNAs in stage II colon cancer,” Cancer Research, vol. 68, no. 15, pp. 6416–6424, 2008.
[66]
O. Slaby, M. Svoboda, P. Fabian et al., “Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer,” Oncology, vol. 72, no. 5-6, pp. 397–402, 2008.
[67]
X. Chen, J. Gong, H. Zeng et al., “MicroRNA145 targets BNIP3 and suppresses prostate cancer progression,” Cancer Research, vol. 70, no. 7, pp. 2728–2738, 2010.
[68]
J. M. Franco-Zorrilla, A. Valli, M. Todesco et al., “Target mimicry provides a new mechanism for regulation of microRNA activity,” Nature Genetics, vol. 39, no. 8, pp. 1033–1037, 2007.
[69]
S. Debernardi, S. Skoulakis, G. Molloy, T. Chaplin, A. Dixon-McIver, and B. D. Young, “MicroRNA miR-181a correlates with morphological sub-class of acute myeloid leukaemia and the expression of its target genes in global genome-wide analysis,” Leukemia, vol. 21, no. 5, pp. 912–916, 2007.
[70]
T. C. Chang, E. A. Wentzel, O. A. Kent et al., “Transactivation of miR-34a by p53 BroadlyInfluences Gene Expression andPromotesApoptosis,” Molecular Cell, vol. 26, no. 5, pp. 745–752, 2007.
[71]
D. Kong, Y. Li, E. Heath, S. Sethi, W. Chen, and F. H. Sarkar, “Epigenetic silencing of miR-34a in human prostate cancer cells and tumor tissue specimens can be reversed by BR-DIM treatment,” American Journal of Translational Research, vol. 4, no. 1, pp. 14–23, 2012.
[72]
S. Varambally, Q. Cao, R. S. Mani et al., “Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer,” Science, vol. 322, no. 5908, pp. 1695–1699, 2008.
[73]
L. A. Boyer, K. Plath, J. Zeitlinger et al., “Polycomb complexes repress developmental regulators in murine embryonic stem cells,” Nature, vol. 441, no. 7091, pp. 349–353, 2006.
[74]
E. Bandrés, E. Cubedo, X. Agirre et al., “Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues,” Molecular Cancer, vol. 5, article 29, 2006.
[75]
I. Koturbash, A. Boyko, R. Rodriguez-Juarez et al., “Role of epigenetic effectors in maintenance of the long-term persistent bystander effect in spleen in vivo,” Carcinogenesis, vol. 28, no. 8, pp. 1831–1838, 2007.
[76]
V. Coppola, R. De Maria, and D. Bonci, “MicroRNAs and prostate cancer,” Endocrine-Related Cancer, vol. 17, no. 1, pp. F1–F17, 2010.
[77]
S. Michiels, S. Koscielny, and C. Hill, “Prediction of cancer outcome with microarrays: a multiple random validation strategy,” Lancet, vol. 365, no. 9458, pp. 488–492, 2005.
[78]
M. Zhang, L. Zhang, J. Zou et al., “Evaluating reproducibility of differential expression discoveries in microarray studies by considering correlated molecular changes,” Bioinformatics, vol. 25, no. 13, pp. 1662–1668, 2009.
[79]
D. Soh, D. Dong, and Y. Guo, “Finding consistent disease subnetworks across microarray datasets,” BMC Bioinformatics, vol. 12, article S15, supplement 13, 2011.
[80]
R. Arora, M. O. Koch, J. N. Eble, T. M. Ulbright, L. Li, and L. Cheng, “Heterogeneity of Gleason grade in multifocal adenocarcinoma of the prostate,” Cancer, vol. 100, no. 11, pp. 2362–2366, 2004.
[81]
L. K. Boyd, X. Mao, L. Xue et al., “High-resolution genome-wide copy-number analysis suggests a monoclonal origin of multifocal prostate cancer,” Genes Chromosomes and Cancer, vol. 51, no. 6, pp. 579–589, 2012.
[82]
K. D. S？rensen and T. F. ？rntoft, “Discovery of prostate cancer biomarkers by microarray gene expression profiling,” Expert Review of Molecular Diagnostics, vol. 10, no. 1, pp. 49–64, 2010.
[83]
Z. H. Chen, G. L. Zhang, and H. R. Li, “A panel of five circulating microRNAs as potential biomarkers for prostate cancer,” Prostate, vol. 72, no. 13, pp. 1443–1452, 2012.
[84]
X. Durand, E. Xylinas, C. Radulescu et al., “The value of urinary prostate cancer gene 3 (PCA3) scores in predicting pathological features at radical prostatectomy,” British Journal of Urology International, vol. 110, no. 1, pp. 43–49, 2012.
