Cancer UrologyCancer UrologyОнкоурология1726-97761996-1812Publishing House ABV Press46110.17650/1726-9776-2015-11-2-99-106PROSTATE CANCERРАК ПРЕДСТАТЕЛЬНОЙ ЖЕЛЕЗЫClinical relevance of prostate cancer genetic characterization: literature reviewКлиническая значимость гене тической характеризации рака предстательной железы: обзор литературыTolkachYu.ТолкачЮ. В.
Russian Federation
yuri.tolkach@gmail.comRevaS.РеваС. А.
Russian Federation
sgreva79@mail.ruNosovA.НосовА. К.
Russian Federation
ImkampF.
Russian Federation
Van PoppelH.
Russian Federation
Hannover Medical School, Urology and Urologic Oncology Clinic, Hannover, GermanyКлиника урологии, Высшая медицинская школа Ганновера, Ганновер, ГерманияCarl-Neuberg-Str. 1, 30625 Hannover, GermanyDepartment of Oncourology FSBI “N.N. Petrov Cancer Research Institute” of thу Ministry of Health of Russiaотделение онкоурологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России68, Leningradskaya St., village Pesochny, Saint-Petersburg 197758, RussiaРоссия, 197758, Санкт-Петербург, пос. Песочный, ул. Ленинградская, 68Department of Urology, University Hospitals of Catholic University of Leuven, Leuven, BelgiumКлиника урологии, Университетская клиника Левена, Левен, Бельгия. UZ Leuven, Campus Gasthuisberg, Herestraat 49, 3000 Leuven, BelgiumUZ Leuven, Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium30062015112991061906201519062015https://oncourology.abvpress.ru/oncur/article/view/461

Molecular and genetic characterization of the prostate cancer seems to be a very relevant issue for clinical practice with regard to diagnostics, prognosis, treatment selection and assessment of therapy efficacy. A lot of fundamental studies assault the genetic basis of the disease and the differences in the phenotypic traits of prostate tumors. However, the significant gap is seen between the huge amount of studies to genetic characterization of prostate cancer, which often have a limited way to translation into the clinical practice or simply were not conceived to be so, and clinical practice. Substantial difficulties on the way are multifocality of the prostate carcinoma, inter- and intrafocal heterogeneity and abundance of recurrent genetic alterations, the role of which is understudied to date. In this review we have aimed at the providing an overview of the current studies, being the most close to translation in clinical practice. The common applications and problems are discussed.

В последнее время предпринимаются многочисленные попытки выявления молекулярных генетических особенностей рака предстательной железы (РПЖ). Тем не менее, несмотря на большое количество исследовательских программ по молекулярной биологии и генетике, значение результатов этих работ остается неясным, а выводы имеют ограниченное применение в клинической практике. Во многом это связано с тем, что РПЖ характеризуется выраженной генетической гетерогенностью. Мы провели анализ литературы для выявления путей возможного клинического применения результатов фундаментальных генетических и молекулярно-биологических исследований в отношении РПЖ (трансляции в клинику), основных проблем, возникающих при этом, и перспектив развития данного направления.

prostate cancergeneticsmolecular biologytranslationprognosisdiagnosticstreatmentpersonalized medicinebiomarkerрак предстательной железыгенетикамолекулярная биологиятрансляцияпрогноздиагностикалечениеперсонализированная медицинабиомаркер1. Barbieri C. E., Tomlins S. A. The prostate cancer genome: perspectives and potential. Urol Oncol 2014;32: e15–22.Barbieri C. E., Tomlins S. A. The prostate cancer genome: perspectives and potential. Urol Oncol 2014;32: e15–22.2. Klopfleisch R., Weiss A. T., Gruber A. D. Excavation of a buried treasure-DNA, mRNA, miRNA and protein analysis in formalin fixed, paraffin embedded tissues. Histol Histopathol 2011;26:797–810.Klopfleisch R., Weiss A. T., Gruber A. D. Excavation of a buried treasure-DNA, mRNA, miRNA and protein analysis in formalin fixed, paraffin embedded tissues. Histol Histopathol 2011;26:797–810.3. Sørensen K. D., Ørntoft T. F. Discovery of prostate cancer biomarkers by microarray gene expression profiling. Expert Rev Mol Diagn 2010;10:49–64.Sørensen K. D., Ørntoft T. F. Discovery of prostate cancer biomarkers by microarray gene expression profiling. Expert Rev Mol Diagn 2010;10:49–64.4. Febbo P. G. Genomic approaches to outcome prediction in prostate cancer. Cancer 2009;115:3046–57.Febbo P. G. Genomic approaches to outcome prediction in prostate cancer. Cancer 2009;115:3046–57.5. Bismar T. A., Demichelis F., Riva A. et al. Defining aggressive prostate cancer using a 12-gene model. Neoplasia 2006;8:59–68.Bismar T. A., Demichelis F., Riva A. et al. Defining aggressive prostate cancer using a 12-gene model. Neoplasia 2006;8:59–68.6. Glinsky G. V., Glinskii A. B., Stephenson A. J. et al. Gene expression profiling predicts clinical outcome of prostate cancer. J Clin Invest 2004;113:913–23.Glinsky G. V., Glinskii A. B., Stephenson A. J. et al. Gene expression profiling predicts clinical outcome of prostate cancer. J Clin Invest 2004;113:913–23.7. Kosari F., Munz J. M., Savci-Heijink C. D. et al. Identification of prognostic biomarkers for prostate cancer. Clin Cancer Res 2008;14:1734–43.Kosari F., Munz J. M., Savci-Heijink C. D. et al. Identification of prognostic biomarkers for prostate cancer. Clin Cancer Res 2008;14:1734–43.8. Gasi Tandefelt D., Boormans J. L., van der Korput H. A. et al. A 36-gene signature predicts clinical progression in a subgroup of ERG-positive prostate cancers. Eur Urol 2013;64:941–50.Gasi Tandefelt D., Boormans J. L., van der Korput H. A. et al. A 36-gene signature predicts clinical progression in a subgroup of ERG-positive prostate cancers. Eur Urol 2013;64:941–50.9. Tomlins S. A., Mehra R., Rhodes D. R. et al. Integrative molecular concept modeling of prostate cancer progression. Nat Genet 2007;39:41–51.Tomlins S. A., Mehra R., Rhodes D. R. et al. Integrative molecular concept modeling of prostate cancer progression. Nat Genet 2007;39:41–51.10. Varambally S., Yu J., Laxman B. et al. Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression. Cancer Cell 2005;8:393–406.Varambally S., Yu J., Laxman B. 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. et al. Comprehensive molecular oncogenomic profiling and miRNA analysis of prostate cancer. Am J Transl Res 2013;5:200–11.Sethi S., Kong D., Land S. et al. Comprehensive molecular oncogenomic profiling and miRNA analysis of prostate cancer. Am J Transl Res 2013;5:200–11.12. Bismar T. A., Alshalalfa M., Petersen L. F. 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, 113:309–19.Bismar T. A., Alshalalfa M., Petersen L. F. 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, 113:309–19.13. Bishoff J. T., Freedland S. J., Gerber L. et al. Prognostic utility of the CCP score generated from biopsy in men treated with prostatectomy. J Urol 2014;192:409–14.Bishoff J. T., Freedland S. J., Gerber L. et al. Prognostic utility of the CCP score generated from biopsy in men treated with prostatectomy. J Urol 2014;192:409–14.14. Chandran U. R., Ma C., Dhir R. et al. Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process. BMC Cancer 2007;7:64.Chandran U. R., Ma C., Dhir R. 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 C. L., Schroeder B. E., Ma X. J. et al. Development and validation of a 32-gene prognostic index for prostate cancer progression. Proc Natl Acad Sci USA 2013;110:6121–6.Wu C. L., Schroeder B. E., Ma X. J. et al. Development and validation of a 32-gene prognostic index for prostate cancer progression. Proc Natl Acad Sci USA 2013;110:6121–6.16. Klein E. A., Cooperberg M. R., Magi- Galluzzi C. 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;66:550–60.Klein E. A., Cooperberg M. R., Magi- Galluzzi C. 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;66:550–60.17. Erho N., Crisan A., Vergara I. A,. et al. Discovery and validation of a prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy. PLoS One 2013, 8: e66855.Erho N., Crisan A., Vergara I. A,. 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 R. J., Bergstralh E. J., Davicioni E. t al. Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. Urol 2013;190:2047–53.Karnes R. J., Bergstralh E. J., Davicioni E. t al. Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. Urol 2013;190:2047–53.19. Cuzick J., Swanson G. P., Fisher G. 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;12:245–55.Cuzick J., Swanson G. P., Fisher G. 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;12:245–55.20. Cuzick J., Berney D. M., Fisher G. 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;106:1095–9.Cuzick J., Berney D. M., Fisher G. 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;106:1095–9.21. Cooperberg M. R., Simko J. P., Cowan J. E. et al. Validation of a cell-cycle progression gene panel to improve risk stratification in a contemporary prostatectomy cohort. J Clin Oncol 2013;31:1428–34.Cooperberg M. R., Simko J. P., Cowan J. E. et al. Validation of a cell-cycle progression gene panel to improve risk stratification in a contemporary prostatectomy cohort. J Clin Oncol 2013;31:1428–34.22. Van den Bergh R. C., Ahmed H. U., Bangma C. H. et al. Novel tools to improve patient selection and monitoring on active surveillance for low-risk prostate cancer: a systematic review. Eur Urol 2014;65:1023–31.Van den Bergh R. C., Ahmed H. U., Bangma C. H. et al. Novel tools to improve patient selection and monitoring on active surveillance for low-risk prostate cancer: a systematic review. Eur Urol 2014;65:1023–31.23. Badani K. K., Thompson D. J., Brown G. et al. Effect of a genomic classifier test on clinical practice decisions for patients with high-risk prostate cancer after surgery. BJU Int, in press.Badani K. K., Thompson D. J., Brown G. et al. Effect of a genomic classifier test on clinical practice decisions for patients with high-risk prostate cancer after surgery. BJU Int, in press.24. Tomlins S. A., Rhodes D. R., Perner S. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005;310:644–8.Tomlins S. A., Rhodes D. R., Perner S. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005;310:644–8.25. Kumar-Sinha C., Tomlins S. A., Chinnaiyan A. M. Recurrent gene fusions in prostate cancer. Nat Rev Cancer 2008;8:497–511.Kumar-Sinha C., Tomlins S. A., Chinnaiyan A. M. Recurrent gene fusions in prostate cancer. Nat Rev Cancer 2008;8:497–511.26. Zhang S., Pavlovitz B., Tull J. et al. 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;19:151–6.Zhang S., Pavlovitz B., Tull J. et al. 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;19:151–6.27. Mosquera J. M., Perner S., Genega E. M. et al. Characterization of TMPRSS2-ERG fusion high-grade prostatic intraepithelial neoplasia and potential clinical implications. Clin Cancer Res 2008;14:3380–5.Mosquera J. M., Perner S., Genega E. M. et al. Characterization of TMPRSS2-ERG fusion high-grade prostatic intraepithelial neoplasia and potential clinical implications. Clin Cancer Res 2008;14:3380–5.28. Velaeti S., Dimitriadis E., Kontogianni-Katsarou K. et al. Detection of TMPRSS2-ERG fusion gene in benign prostatic hyperplasia. Tumour Biol;2014; 35:9597–602.Velaeti S., Dimitriadis E., Kontogianni-Katsarou K. et al. Detection of TMPRSS2-ERG fusion gene in benign prostatic hyperplasia. Tumour Biol;2014; 35:9597–602.29. Tomlins S. A., Bjartell A., Chinnaiyan A. M. et al. ETS gene fusions in prostate cancer. from discovery to daily clinical practice. Eur Urol 2009;56:275–86.Tomlins S. A., Bjartell A., Chinnaiyan A. M. et al. ETS gene fusions in prostate cancer. from discovery to daily clinical practice. Eur Urol 2009;56:275–86.30. Lucas J. M., Heinlein C., Kim T. et al. The Androgen-Regulated Protease TMPRSS2 Activates a Proteolytic Cascade Involving Components of the Tumor Microenvironment and Promotes Prostate Cancer Metastasis. Cancer Discov, in press.Lucas J. M., Heinlein C., Kim T. et al. The Androgen-Regulated Protease TMPRSS2 Activates a Proteolytic Cascade Involving Components of the Tumor Microenvironment and Promotes Prostate Cancer Metastasis. Cancer Discov, in press.31. Han B., Mehra R., Dhanasekaran S. M. 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;68:7629–37.Han B., Mehra R., Dhanasekaran S. M. 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;68:7629–37.32. Barros-Silva J. D., Paulo P., Bakken A. C. et al. Novel 5» fusion partners of ETV1 and ETV4 in prostate cancer. Neoplasia 2013;15:720–6.Barros-Silva J. D., Paulo P., Bakken A. C. et al. Novel 5» fusion partners of ETV1 and ETV4 in prostate cancer. Neoplasia 2013;15:720–6.33. Mehra R., Tomlins S. A., Shen R. et al. omprehensive assessment of TMPRSS2 and ETS family gene aberrations in clinically localized prostate cancer. Mod Pathol 2007;20:538–44.Mehra R., Tomlins S. A., Shen R. et al. omprehensive assessment of TMPRSS2 and ETS family gene aberrations in clinically localized prostate cancer. Mod Pathol 2007;20:538–44.34. Klezovitch O., Risk M., Coleman I. et al. A causal role for ERG in neoplastic transformation of prostate epithelium. Proc Natl Acad Sci USA 2008;105:2105–10.Klezovitch O., Risk M., Coleman I. et al. A causal role for ERG in neoplastic transformation of prostate epithelium. Proc Natl Acad Sci USA 2008;105:2105–10.35. King J. C., Xu J., Wongvipat J. et al. Cooperativity of TMPRSS2-ERG with PI3- kinase pathway activation in prostate oncogenesis. Nat Genet 2009;41:524–6.King J. C., Xu J., Wongvipat J. et al. Cooperativity of TMPRSS2-ERG with PI3- kinase pathway activation in prostate oncogenesis. Nat Genet 2009;41:524–6.36. Carver B. S., Tran J., Gopalan A. et al. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat Genet 2009;41:619–24.Carver B. S., Tran J., Gopalan A. et al. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat Genet 2009;41:619–24.37. Eguchi F. C., Faria E. F., Scapulatempo Neto C. 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.Eguchi F. C., Faria E. F., Scapulatempo Neto C. 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 P. S., Adam M. et al. TMPRSS2-ERG fusions are strongly linked to young patient age in low-grade prostate cancer. Eur Urol, in press.Steurer S., Mayer P. S., Adam M. et al. TMPRSS2-ERG fusions are strongly linked to young patient age in low-grade prostate cancer. Eur Urol, in press.39. Pettersson A., Graff R. E., Bauer S. R. et al. The TMPRSS2: ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis. Cancer Epidemiol Biomarkers Prev 2012;21:1497–509.Pettersson A., Graff R. E., Bauer S. R. et al. The TMPRSS2: ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis. Cancer Epidemiol Biomarkers Prev 2012;21:1497–509.40. Hoogland A. M., Jenster G., van Weerden W. M. et al. ERG immunohistochemistry is not predictive for PSA recurrence, local recurrence or overall survival after radical prostatectomy for prostate cancer. Mod Pathol 2012;25:471–9.Hoogland A. M., Jenster G., van Weerden W. M. et al. ERG immunohistochemistry is not predictive for PSA recurrence, local recurrence or overall survival after radical prostatectomy for prostate cancer. Mod Pathol 2012;25:471–9.41. Dijkstra S., Mulders P. F., Schalken J. A. Clinical use of novel urine and blood based prostate cancer biomarkers: A review. Clin Biochem 2014;27:889–96.Dijkstra S., Mulders P. F., Schalken J. A. Clinical use of novel urine and blood based prostate cancer biomarkers: A review. Clin Biochem 2014;27:889–96.42. Baca S. C., Prandi D., Lawrence M. S. et al. Punctuated evolution of prostate cancer genomes. Cell 2013;153:666–77.Baca S. C., Prandi D., Lawrence M. S. et al. Punctuated evolution of prostate cancer genomes. Cell 2013;153:666–77.43. Taylor B. S., Schultz N., Hieronymus H. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010;18:11–22.Taylor B. S., Schultz N., Hieronymus H. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010;18:11–22.44. Grasso C. S., Wu Y. M., Robinson D. R. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012;487:239–43.Grasso C. S., Wu Y. M., Robinson D. R. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012;487:239–43.45. Lorente D., De Bono J. S. Molecular alterations and emerging targets in castration resistant prostate cancer. Eur J Cancer 2014;50:753–64.Lorente D., De Bono J. S. Molecular alterations and emerging targets in castration resistant prostate cancer. Eur J Cancer 2014;50:753–64.46. Van der Kwast T. H. Prognostic prostate tissue biomarkers of potential clinical use. Virchows Arch 2014;464:293–300.Van der Kwast T. H. Prognostic prostate tissue biomarkers of potential clinical use. Virchows Arch 2014;464:293–300.47. Zafarana G., Ishkanian A. S., Malloff C. A. et al. Copy number alterations of c-MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy. Cancer 2012;118:4053–62.Zafarana G., Ishkanian A. S., Malloff C. A. et al. Copy number alterations of c-MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy. Cancer 2012;118:4053–62.48. Lapointe J., Li C., Giacomini C. P. et al. Genomic profiling reveals alternative genetic pathways of prostate tumorigenesis. Cancer Res 2007;67:8504–10.Lapointe J., Li C., Giacomini C. P. et al. Genomic profiling reveals alternative genetic pathways of prostate tumorigenesis. Cancer Res 2007;67:8504–10.49. Sowalsky A. G., Ye H., Bubley G. J., Balk S. P. Clonal progression of prostatecancers from Gleason grade 3 to grade 4. Cancer Res 2013;73:1050–5.Sowalsky A. G., Ye H., Bubley G. J., Balk S. P. Clonal progression of prostatecancers from Gleason grade 3 to grade 4. Cancer Res 2013;73:1050–5.50. Lalonde E., Ishkanian A. S., Sykes J. et al. Tumour genomic and microenvironmentalheterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. Lancet Oncol 2014;15:1521–32.Lalonde E., Ishkanian A. S., Sykes J. et al. Tumour genomic and microenvironmentalheterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. Lancet Oncol 2014;15:1521–32.51. Hieronymus H., Schultz N., Gopalan A. et al. Copy number alteration burden predicts prostate cancer relapse. Proc Natl Acad Sci USA 2014;111:11139–44.Hieronymus H., Schultz N., Gopalan A. et al. Copy number alteration burden predicts prostate cancer relapse. Proc Natl Acad Sci USA 2014;111:11139–44.52. Markert E. K., Mizuno H., Vazquez A., Levine A. J. Molecular classification of prostate cancer using curated expression signatures. Proc Natl Acad Sci USA 2011;108:21276–81.Markert E. K., Mizuno H., Vazquez A., Levine A. J. Molecular classification of prostate cancer using curated expression signatures. Proc Natl Acad Sci USA 2011;108:21276–81.53. Nagle R. B., Algotar A. M., Cortez C. C. et al. ERG overexpression and PTEN status predict capsular penetration in prostate carcinoma. Prostate 2013;73:1233–40.Nagle R. B., Algotar A. M., Cortez C. C. et al. ERG overexpression and PTEN status predict capsular penetration in prostate carcinoma. Prostate 2013;73:1233–40.54. Grupp K., Wilking J., Prien K. 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;50:852–61.Grupp K., Wilking J., Prien K. 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;50:852–61.55. Grupp K., Kohl S., Sirma H. et al. Cysteine-rich secretory protein 3 overexpression is linked to a subset of PTENdeleted ERG fusion-positive prostate cancers with early biochemical recurrence. Mod Pathol 2013;26:733–42.Grupp K., Kohl S., Sirma H. et al. Cysteine-rich secretory protein 3 overexpression is linked to a subset of PTENdeleted ERG fusion-positive prostate cancers with early biochemical recurrence. Mod Pathol 2013;26:733–42.56. Gumuskaya B., Gurel B., Fedor H. 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;16:209–15.Gumuskaya B., Gurel B., Fedor H. 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;16:209–15.57. Stumm L., Burkhardt L., Steurer S. 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;66:563–8.Stumm L., Burkhardt L., Steurer S. 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;66:563–8.58. Krohn A., Seidel A., Burkhardt L. 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;231:130–41.Krohn A., Seidel A., Burkhardt L. 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;231:130–41.59. Andreoiu M., Cheng L. Multifocal prostate cancer: biologic, prognostic, and therapeutic implications. Hum Pathol 2010;41:781–93.Andreoiu M., Cheng L. Multifocal prostate cancer: biologic, prognostic, and therapeutic implications. Hum Pathol 2010;41:781–93.60. Wolters T., Montironi R., Mazzucchelli R. et al. Comparison of incidentally detected prostate cancer with screen-detected prostate cancer treated by prostatectomy. Prostate 2012;72:108–15.Wolters T., Montironi R., Mazzucchelli R. et al. Comparison of incidentally detected prostate cancer with screen-detected prostate cancer treated by prostatectomy. Prostate 2012;72:108–15.61. Ibeawuchi C., Schmidt H., Voss R. et al. Genome-wide investigation of multifocal and unifocal prostate cancer-are they genetically different? Int J Mol Sci 2013;14:11816–29.Ibeawuchi C., Schmidt H., Voss R. et al. Genome-wide investigation of multifocal and unifocal prostate cancer-are they genetically different? Int J Mol Sci 2013;14:11816–29.62. Yoshimoto M., Ding K., Sweet J. M. et al. PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade. Mod Pathol 2013;26:435–47.Yoshimoto M., Ding K., Sweet J. M. et al. PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade. Mod Pathol 2013;26:435–47.63. Minner S., Gärtner M., Freudenthaler F. et al. Marked heterogeneity of ERG expression in large primary prostate cancers. Mod Pathol 2013;26:106–16.Minner S., Gärtner M., Freudenthaler F. et al. Marked heterogeneity of ERG expression in large primary prostate cancers. Mod Pathol 2013;26:106–16.64. Brocks D., Assenov Y., Minner S. et al. Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer. Cell Rep 2014;8:798–806.Brocks D., Assenov Y., Minner S. et al. Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer. Cell Rep 2014;8:798–806.65. Kovtun I. V., Cheville J. C., Murphy S. J. et al. Lineage relationship of Gleason patterns in Gleason score 7 prostate cancer. Cancer Res 2013;73:3275–84.Kovtun I. V., Cheville J. C., Murphy S. J. et al. Lineage relationship of Gleason patterns in Gleason score 7 prostate cancer. Cancer Res 2013;73:3275–84.66. Baylin S. B., Jones P. A. A decade of exploring the cancer epigenome – biological and translational implications. Nat Rev Cancer 2011;11:726–34.Baylin S. B., Jones P. A. A decade of exploring the cancer epigenome – biological and translational implications. Nat Rev Cancer 2011;11:726–34.67. Chiam K., Ricciardelli C., Bianco-Miotto T. Epigenetic biomarkers in prostate cancer: Current and future uses. Cancer Lett 2014;342:248–56.Chiam K., Ricciardelli C., Bianco-Miotto T. Epigenetic biomarkers in prostate cancer: Current and future uses. Cancer Lett 2014;342:248–56.68. Nonn L., Ananthanarayanan V., Gann P. H. Evidence for field cancerization of the prostate. Prostate 2009;69:1470–9.Nonn L., Ananthanarayanan V., Gann P. H. Evidence for field cancerization of the prostate. Prostate 2009;69:1470–9.69. Van Neste L., Herman J. G., Otto G. et al. The epigenetic promise for prostate cancer diagnosis. Prostate 2012;72:1248–61.Van Neste L., Herman J. G., Otto G. et al. The epigenetic promise for prostate cancer diagnosis. Prostate 2012;72:1248–61.70. Mehrotra J., Varde S., Wang H. et al. Quantitative, spatial resolution of the epigenetic field effect in prostate cancer. Prostate 2008;68:152–60.Mehrotra J., Varde S., Wang H. et al. Quantitative, spatial resolution of the epigenetic field effect in prostate cancer. Prostate 2008;68:152–60.71. Stewart G. D., Van Neste L., Delvenne P. 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;189:1110–6.Stewart G. D., Van Neste L., Delvenne P. 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;189:1110–6.72. Trock B. J., Brotzman M. J., Mangold L. A. 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.Trock B. J., Brotzman M. J., Mangold L. A. 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 M. C., Knudsen B. S., Coleman I. et al. Differential gene expression in benign prostate epithelium of men with and without prostate cancer: evidence for a prostate ancer field effect. Clin Cancer Res 2010;16:5414–23.Risk M. C., Knudsen B. S., Coleman I. et al. Differential gene expression in benign prostate epithelium of men with and without prostate cancer: evidence for a prostate ancer field effect. Clin Cancer Res 2010;16:5414–23.74. Partin A. W., Van Neste L., Klein E. A. et al. Clinical validation of an epigenetic assay to predict negative histopathological results in repeat prostate biopsies. J Urol, in press.Partin A. W., Van Neste L., Klein E. A. et al. Clinical validation of an epigenetic assay to predict negative histopathological results in repeat prostate biopsies. J Urol, in press.75. Truong M., Yang B., Livermore A. et al. Using the epigenetic field defect to detect prostate cancer in biopsy negative patients. J Urol 2013;189:2335–41.Truong M., Yang B., Livermore A. et al. Using the epigenetic field defect to detect prostate cancer in biopsy negative patients. J Urol 2013;189:2335–41.76. Zardavas D., Maetens M., Irrthum A. et al. The AURORA initiative for metastatic breast cancer. Br J Cancer 2014;111:1881–7.Zardavas D., Maetens M., Irrthum A. et al. The AURORA initiative for metastatic breast cancer. Br J Cancer 2014;111:1881–7.