Korean J Urol.  2015 Feb;56(2):90-98. 10.4111/kju.2015.56.2.90.

Clinically relevant genetic characterization of prostate tumors: How close are we to the goal?

• Tolkach Y
• Imkamp F
• Godin K
• Van Poppel H

• KMID: 2133272
• DOI: http://doi.org/10.4111/kju.2015.56.2.90

Abstract

Substantial efforts are being made in research on the molecular genetic characterization of prostate cancer. The number of fundamental research programs in prostate cancer molecular biology and genetics is overwhelming. However, a significant gap appears to exist between the huge number of studies on the genetic characterization of prostate cancer, which often have limited translation into clinical practice or simply were not conceived to be so translated, and clinical practice. From a clinical point of view, this balance should be urgently shifted towards rapid translation into urological practice. However, prostate cancer is characterized by prominent genetic heterogeneity, which could be a very difficult barrier to overcome. In this review, we discuss the possible clinical applications of scientific data from fundamental studies of prostate cancer genetics, the main problems with the translation of these data to clinics, and future perspectives.

Keyword

Biological markers; Molecular biology; Prostate neoplasms; Translations

MeSH Terms

Biomarkers, Tumor/genetics
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
Goals
Humans
Male
Prostatic Neoplasms/*genetics
Transcriptome
Biomarkers, Tumor

Figure

• 

  Fig. 1 Contemporary efforts toward the clinical translation of basic studies related to the genetic characterization of prostate tumors. CNV, copy number variaton. *For additional information, see the text of the article.

Reference

1. Barbieri CE, Tomlins SA. The prostate cancer genome: perspectives and potential. Urol Oncol. 2014; 32:53.e15. 53.e22.

2. Klopfleisch R, Weiss AT, Gruber AD. Excavation of a buried treasure: DNA, mRNA, miRNA and protein analysis in formalin fixed, paraffin embedded tissues. Histol Histopathol. 2011; 26:797–810.

3. Sorensen KD, Orntoft TF. Discovery of prostate cancer biomarkers by microarray gene expression profiling. Expert Rev Mol Diagn. 2010; 10:49–64.

4. Febbo PG. Genomic approaches to outcome prediction in prostate cancer. Cancer. 2009; 115:13 Suppl. 3046–3057.

5. Bismar TA, Demichelis F, Riva A, Kim R, Varambally S, He L, et al. Defining aggressive prostate cancer using a 12-gene model. Neoplasia. 2006; 8:59–68.

6. Glinsky GV, Glinskii AB, Stephenson AJ, Hoffman RM, Gerald WL. Gene expression profiling predicts clinical outcome of prostate cancer. J Clin Invest. 2004; 113:913–923.

7. Kosari F, Munz JM, Savci-Heijink CD, Spiro C, Klee EW, Kube DM, et al. Identification of prognostic biomarkers for prostate cancer. Clin Cancer Res. 2008; 14:1734–1743.

8. Gasi Tandefelt D, Boormans JL, van der Korput HA, Jenster GW, Trapman J. A 36-gene signature predicts clinical progression in a subgroup of ERG-positive prostate cancers. Eur Urol. 2013; 64:941–950.

9. Tomlins SA, Mehra R, Rhodes DR, Cao X, Wang L, Dhanasekaran SM, et al. Integrative molecular concept modeling of prostate cancer progression. Nat Genet. 2007; 39:41–51.

10. Varambally S, Yu J, Laxman B, Rhodes DR, Mehra R, Tomlins SA, et al. Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression. Cancer Cell. 2005; 8:393–406.

11. Sethi S, Kong D, Land S, Dyson G, Sakr WA, Sarkar FH. Comprehensive molecular oncogenomic profiling and miRNA analysis of prostate cancer. Am J Transl Res. 2013; 5:200–211.

12. Bismar TA, Alshalalfa M, Petersen LF, Teng LH, Gerke T, Bakkar A, et al. Interrogation of ERG gene rearrangements in prostate cancer identifies a prognostic 10-gene signature with relevant implication to patients' clinical outcome. BJU Int. 2014; 113:309–319.

13. Bishoff JT, Freedland SJ, Gerber L, Tennstedt P, Reid J, Welbourn W, et al. Prognostic utility of the cell cycle progression score generated from biopsy in men treated with prostatectomy. J Urol. 2014; 192:409–414.

14. Chandran UR, Ma C, Dhir R, Bisceglia M, Lyons-Weiler M, Liang W, et al. Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process. BMC Cancer. 2007; 7:64.

15. Wu CL, Schroeder BE, Ma XJ, Cutie CJ, Wu S, Salunga R, et al. Development and validation of a 32-gene prognostic index for prostate cancer progression. Proc Natl Acad Sci U S A. 2013; 110:6121–6126.

16. Klein EA, Cooperberg MR, Magi-Galluzzi C, Simko JP, Falzarano SM, Maddala T, et al. A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. Eur Urol. 2014; 66:550–560.

17. Erho N, Crisan A, Vergara IA, Mitra AP, Ghadessi M, Buerki C, et al. Discovery and validation of a prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy. PLoS One. 2013; 8:e66855.

18. Karnes RJ, Bergstralh EJ, Davicioni E, Ghadessi M, Buerki C, Mitra AP, et al. Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. J Urol. 2013; 190:2047–2053.

19. Cuzick J, Swanson GP, Fisher G, Brothman AR, Berney DM, Reid JE, et al. Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study. Lancet Oncol. 2011; 12:245–255.

20. Cuzick J, Berney DM, Fisher G, Mesher D, Moller H, Reid JE, et al. Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort. Br J Cancer. 2012; 106:1095–1099.

21. Cooperberg MR, Simko JP, Cowan JE, Reid JE, Djalilvand A, Bhatnagar S, et al. Validation of a cell-cycle progression gene panel to improve risk stratification in a contemporary prostatectomy cohort. J Clin Oncol. 2013; 31:1428–1434.

22. van den Bergh RC, Ahmed HU, Bangma CH, Cooperberg MR, Villers A, Parker CC. Novel tools to improve patient selection and monitoring on active surveillance for low-risk prostate cancer: a systematic review. Eur Urol. 2014; 65:1023–1031.

23. Badani KK, Thompson DJ, Brown G, Holmes D, Kella N, Albala D, et al. Effect of a genomic classifier test on clinical practice decisions for patients with high-risk prostate cancer after surgery. BJU Int. 2014; 04. 30. [Epub]. http://dx.doi.org/10.1111/bju.12789.

24. 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. Science. 2005; 310:644–648.

25. Kumar-Sinha C, Tomlins SA, Chinnaiyan AM. Recurrent gene fusions in prostate cancer. Nat Rev Cancer. 2008; 8:497–511.

26. Zhang S, Pavlovitz B, Tull J, Wang Y, Deng FM, Fuller C. Detection of TMPRSS2 gene deletions and translocations in carcinoma, intraepithelial neoplasia, and normal epithelium of the prostate by direct fluorescence in situ hybridization. Diagn Mol Pathol. 2010; 19:151–156.

27. Mosquera JM, Perner S, Genega EM, Sanda M, Hofer MD, Mertz KD, et al. Characterization of TMPRSS2-ERG fusion high-grade prostatic intraepithelial neoplasia and potential clinical implications. Clin Cancer Res. 2008; 14:3380–3385.

28. Velaeti S, Dimitriadis E, Kontogianni-Katsarou K, Savvani A, Sdrolia E, Pantazi G, et al. Detection of TMPRSS2-ERG fusion gene in benign prostatic hyperplasia. Tumour Biol. 2014; 35:9597–9602.

29. Tomlins SA, Bjartell A, Chinnaiyan AM, Jenster G, Nam RK, Rubin MA, et al. ETS gene fusions in prostate cancer: from discovery to daily clinical practice. Eur Urol. 2009; 56:275–286.

30. Lucas JM, Heinlein C, Kim T, Hernandez SA, Malik MS, True LD, et al. The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. Cancer Discov. 2014; 4:1310–1325.

31. Han B, Mehra R, Dhanasekaran SM, Yu J, Menon A, Lonigro RJ, et al. A fluorescence in situ hybridization screen for E26 transformation-specific aberrations: identification of DDX5-ETV4 fusion protein in prostate cancer. Cancer Res. 2008; 68:7629–7637.

32. Barros-Silva JD, Paulo P, Bakken AC, Cerveira N, Lovf M, Henrique R, et al. Novel 5' fusion partners of ETV1 and ETV4 in prostate cancer. Neoplasia. 2013; 15:720–726.

33. Mehra R, Tomlins SA, Shen R, Nadeem O, Wang L, Wei JT, et al. Comprehensive assessment of TMPRSS2 and ETS family gene aberrations in clinically localized prostate cancer. Mod Pathol. 2007; 20:538–544.

34. Klezovitch O, Risk M, Coleman I, Lucas JM, Null M, True LD, et al. A causal role for ERG in neoplastic transformation of prostate epithelium. Proc Natl Acad Sci U S A. 2008; 105:2105–2110.

35. King JC, Xu J, Wongvipat J, Hieronymus H, Carver BS, Leung DH, et al. Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis. Nat Genet. 2009; 41:524–526.

36. Carver BS, Tran J, Gopalan A, Chen Z, Shaikh S, Carracedo A, et al. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat Genet. 2009; 41:619–624.

37. Eguchi FC, Faria EF, Scapulatempo Neto C, Longatto-Filho A, Zanardo-Oliveira C, Taboga SR, et al. The role of TMPRSS2:ERG in molecular stratification of PCa and its association with tumor aggressiveness: a study in Brazilian patients. Sci Rep. 2014; 4:5640.

38. Steurer S, Mayer PS, Adam M, Krohn A, Koop C, Ospina-Klinck D, et al. TMPRSS2-ERG fusions are strongly linked to young patient age in low-grade prostate cancer. Eur Urol. 2014; 66:978–981.

39. Pettersson A, Graff RE, Bauer SR, Pitt MJ, Lis RT, Stack EC, et al. The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2012; 21:1497–1509.

40. Hoogland AM, Jenster G, van Weerden WM, Trapman J, van der Kwast T, Roobol MJ, et al. ERG immunohistochemistry is not predictive for PSA recurrence, local recurrence or overall survival after radical prostatectomy for prostate cancer. Mod Pathol. 2012; 25:471–479.

41. Dijkstra S, Mulders PF, Schalken JA. Clinical use of novel urine and blood based prostate cancer biomarkers: a review. Clin Biochem. 2014; 47:889–896.

42. Baca SC, Prandi D, Lawrence MS, Mosquera JM, Romanel A, Drier Y, et al. Punctuated evolution of prostate cancer genomes. Cell. 2013; 153:666–677.

43. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010; 18:11–22.

44. Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012; 487:239–243.

45. Lorente D, De Bono JS. Molecular alterations and emerging targets in castration resistant prostate cancer. Eur J Cancer. 2014; 50:753–764.

46. Van der Kwast TH. Prognostic prostate tissue biomarkers of potential clinical use. Virchows Arch. 2014; 464:293–300.

47. Zafarana G, Ishkanian AS, Malloff CA, Locke JA, Sykes J, Thoms J, et al. Copy number alterations of c-MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy. Cancer. 2012; 118:4053–4062.

48. Lapointe J, Li C, Giacomini CP, Salari K, Huang S, Wang P, et al. Genomic profiling reveals alternative genetic pathways of prostate tumorigenesis. Cancer Res. 2007; 67:8504–8510.

49. Sowalsky AG, Ye H, Bubley GJ, Balk SP. Clonal progression of prostate cancers from Gleason grade 3 to grade 4. Cancer Res. 2013; 73:1050–1055.

50. Lalonde E, Ishkanian AS, Sykes J, Fraser M, Ross-Adams H, Erho N, et al. Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. Lancet Oncol. 2014; 15:1521–1532.

51. Hieronymus H, Schultz N, Gopalan A, Carver BS, Chang MT, Xiao Y, et al. Copy number alteration burden predicts prostate cancer relapse. Proc Natl Acad Sci U S A. 2014; 111:11139–11144.

52. Markert EK, Mizuno H, Vazquez A, Levine AJ. Molecular classification of prostate cancer using curated expression signatures. Proc Natl Acad Sci U S A. 2011; 108:21276–21281.

53. Nagle RB, Algotar AM, Cortez CC, Smith K, Jones C, Sathyanarayana UG, et al. ERG overexpression and PTEN status predict capsular penetration in prostate carcinoma. Prostate. 2013; 73:1233–1240.

54. Grupp K, Wilking J, Prien K, Hube-Magg C, Sirma H, Simon R, et al. High RNA-binding motif protein 3 expression is an independent prognostic marker in operated prostate cancer and tightly linked to ERG activation and PTEN deletions. Eur J Cancer. 2014; 50:852–861.

55. Grupp K, Kohl S, Sirma H, Simon R, Steurer S, Becker A, et al. Cysteine-rich secretory protein 3 overexpression is linked to a subset of PTEN-deleted ERG fusion-positive prostate cancers with early biochemical recurrence. Mod Pathol. 2013; 26:733–742.

56. Gumuskaya B, Gurel B, Fedor H, Tan HL, Weier CA, Hicks JL, et al. Assessing the order of critical alterations in prostate cancer development and progression by IHC: further evidence that PTEN loss occurs subsequent to ERG gene fusion. Prostate Cancer Prostatic Dis. 2013; 16:209–215.

57. Stumm L, Burkhardt L, Steurer S, Simon R, Adam M, Becker A, et al. Strong expression of the neuronal transcription factor FOXP2 is linked to an increased risk of early PSA recurrence in ERG fusion-negative cancers. J Clin Pathol. 2013; 66:563–568.

58. Krohn A, Seidel A, Burkhardt L, Bachmann F, Mader M, Grupp K, et al. Recurrent deletion of 3p13 targets multiple tumour suppressor genes and defines a distinct subgroup of aggressive ERG fusion-positive prostate cancers. J Pathol. 2013; 231:130–141.

59. Andreoiu M, Cheng L. Multifocal prostate cancer: biologic, prognostic, and therapeutic implications. Hum Pathol. 2010; 41:781–793.

60. Wolters T, Montironi R, Mazzucchelli R, Scarpelli M, Roobol MJ, van den Bergh RC, et al. Comparison of incidentally detected prostate cancer with screen-detected prostate cancer treated by prostatectomy. Prostate. 2012; 72:108–115.

61. Ibeawuchi C, Schmidt H, Voss R, Titze U, Abbas M, Neumann J, et al. Genome-wide investigation of multifocal and unifocal prostate cancer-are they genetically different? Int J Mol Sci. 2013; 14:11816–11829.

62. Yoshimoto M, Ding K, Sweet JM, Ludkovski O, Trottier G, Song KS, et al. PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade. Mod Pathol. 2013; 26:435–447.

63. Minner S, Gartner M, Freudenthaler F, Bauer M, Kluth M, Salomon G, et al. Marked heterogeneity of ERG expression in large primary prostate cancers. Mod Pathol. 2013; 26:106–116.

64. Brocks D, Assenov Y, Minner S, Bogatyrova O, Simon R, Koop C, et al. Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer. Cell Rep. 2014; 8:798–806.

65. Kovtun IV, Cheville JC, Murphy SJ, Johnson SH, Zarei S, Kosari F, et al. Lineage relationship of Gleason patterns in Gleason score 7 prostate cancer. Cancer Res. 2013; 73:3275–3284.

66. Baylin SB, Jones PA. A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer. 2011; 11:726–734.

67. Chiam K, Ricciardelli C, Bianco-Miotto T. Epigenetic biomarkers in prostate cancer: Current and future uses. Cancer Lett. 2014; 342:248–256.

68. Nonn L, Ananthanarayanan V, Gann PH. Evidence for field cancerization of the prostate. Prostate. 2009; 69:1470–1479.

69. Van Neste L, Herman JG, Otto G, Bigley JW, Epstein JI, Van Criekinge W. The epigenetic promise for prostate cancer diagnosis. Prostate. 2012; 72:1248–1261.

70. Mehrotra J, Varde S, Wang H, Chiu H, Vargo J, Gray K, et al. Quantitative, spatial resolution of the epigenetic field effect in prostate cancer. Prostate. 2008; 68:152–160.

71. Stewart GD, Van Neste L, Delvenne P, Delree P, Delga A, McNeill SA, et al. Clinical utility of an epigenetic assay to detect occult prostate cancer in histopathologically negative biopsies: results of the MATLOC study. J Urol. 2013; 189:1110–1116.

72. Trock BJ, Brotzman MJ, Mangold LA, Bigley JW, Epstein JI, McLeod D, et al. Evaluation of GSTP1 and APC methylation as indicators for repeat biopsy in a high-risk cohort of men with negative initial prostate biopsies. BJU Int. 2012; 110:56–62.

73. Risk MC, Knudsen BS, Coleman I, Dumpit RF, Kristal AR, LeMeur N, et al. Differential gene expression in benign prostate epithelium of men with and without prostate cancer: evidence for a prostate cancer field effect. Clin Cancer Res. 2010; 16:5414–5423.

74. Partin AW, Van Neste L, Klein EA, Marks LS, Gee JR, Troyer DA, et al. Clinical validation of an epigenetic assay to predict negative histopathological results in repeat prostate biopsies. J Urol. 2014; 192:1081–1087.

75. Truong M, Yang B, Livermore A, Wagner J, Weeratunga P, Huang W, et al. Using the epigenetic field defect to detect prostate cancer in biopsy negative patients. J Urol. 2013; 189:2335–2341.

76. Zardavas D, Maetens M, Irrthum A, Goulioti T, Engelen K, Fumagalli D, et al. The AURORA initiative for metastatic breast cancer. Br J Cancer. 2014; 111:1881–1887.