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Prostate Cancer: A Comprehensive Perspective pp 207–213Cite as

Molecular Risk Profiling

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Abstract

Given the clinical heterogeneity and increasing stage migration to lower-risk disease with PSA screening, there is a pressing need for reliable prognostic factors in prostate cancer. An increased understanding of the molecular pathogenesis of the disease has resulted in the identification of a variety of molecular markers representing many of the hallmarks of cancer. Current markers which hold promise include cell cycle control molecules, pro-growth signals, and markers for invasion and metastasis. Evolving technologies such as circulating tumor cells also hold great promise. This chapter summarizes markers from the tumor, urine, and blood which may help better characterize an individual patient’s clinical course.

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References

  1. Shao YH, Demissie K, Shih W, et al. Contemporary risk profile of prostate cancer in the United States. J Natl Cancer Inst. 2009;101(18):1280–3.

    Article  PubMed  Google Scholar 

  2. Zelefsky MJ, Eastham JA, Cronin AM, et al. Metastasis after radical prostatectomy or external beam radiotherapy for patients with clinically localized prostate cancer: a comparison of clinical cohorts adjusted for case mix. J Clin Oncol. 2010;28(9):1508–13.

    Article  PubMed  Google Scholar 

  3. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280(11):969–74.

    Article  PubMed  Google Scholar 

  4. Andriole GL, Crawford ED, Grubb 3rd RL, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360(13):1310–9.

    Article  PubMed  CAS  Google Scholar 

  5. Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360(13):1320–8.

    Article  PubMed  Google Scholar 

  6. Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol. 2010;11(8):725–32.

    Article  PubMed  Google Scholar 

  7. Gleason DF, Mellinger GT. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol. 1974;111(1):58–64.

    PubMed  CAS  Google Scholar 

  8. Stark JR, Perner S, Stampfer MJ, et al. Gleason score and lethal prostate cancer: does 3  +  4  =  4  +  3? J Clin Oncol. 2009;27(21):3459–64.

    Article  PubMed  Google Scholar 

  9. Partin AW, Kattan MW, Subong EN, et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA. 1997;277(18):1445–51.

    Article  PubMed  CAS  Google Scholar 

  10. D’Amico AV, Chen M-H, Roehl KA, Catalona WJ. Preoperative PSA, velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med. 2004;351(2):125–35.

    Article  PubMed  Google Scholar 

  11. Shipley WU, Thames HD, Sandler HM, et al. Radiation therapy for clinically localized prostate cancer: a multi-institutional pooled analysis. JAMA. 1999;281(17):1598–604.

    Article  PubMed  CAS  Google Scholar 

  12. Shukla-Dave A, Hricak H, Ishill N, et al. Prediction of prostate cancer recurrence using magnetic resonance imaging and molecular profiles. Clin Cancer Res. 2009;15(11):3842–9.

    Article  PubMed  CAS  Google Scholar 

  13. Taplin ME, Bubley GJ, Shuster TD, et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med. 1995;332(21):1393–8.

    Article  PubMed  CAS  Google Scholar 

  14. Pollack A, DeSilvio M, Khor LY, et al. Ki-67 staining is a strong predictor of distant metastasis and mortality for men with prostate cancer treated with radiotherapy plus androgen deprivation: radiation therapy oncology group trial 92–02. J Clin Oncol. 2004;22(11):2133–40.

    Article  PubMed  CAS  Google Scholar 

  15. Bettencourt MC, Bauer JJ, Sesterhenn IA, Mostofi FK, McLeod DG, Moul JW. Ki-67 expression is a prognostic marker of prostate cancer recurrence after radical prostatectomy. J Urol. 1996;156(3):1064–8.

    Article  PubMed  CAS  Google Scholar 

  16. Demichelis F, Fall K, Perner S, et al. TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene. 2007;26(31):4596–9.

    Article  PubMed  CAS  Google Scholar 

  17. Attard G, Clark J, Ambroisine L, et al. Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene. 2008;27(3):253–63.

    Article  PubMed  CAS  Google Scholar 

  18. Gopalan A, Leversha MA, Satagopan JM, et al. TMPRSS2-ERG gene fusion is not associated with outcome in patients treated by prostatectomy. Cancer Res. 2009;69(4):1400–6.

    Article  PubMed  CAS  Google Scholar 

  19. Halvorsen OJ, Haukaas SA, Akslen LA. Combined loss of PTEN and p27 expression is associated with tumor cell proliferation by Ki-67 and increased risk of recurrent disease in localized prostate cancer. Clin Cancer Res. 2003;9(4):1474–9.

    PubMed  CAS  Google Scholar 

  20. McMenamin ME, Soung P, Perera S, Kaplan I, Loda M, Sellers WR. Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage. Cancer Res. 1999;59(17):4291–6.

    PubMed  CAS  Google Scholar 

  21. Ayala G, Thompson T, Yang G, et al. High levels of phosphorylated form of Akt-1 in prostate cancer and non-neoplastic prostate tissues are strong predictors of biochemical recurrence. Clin Cancer Res. 2004;10(19):6572–8.

    Article  PubMed  CAS  Google Scholar 

  22. Li R, Dai H, Wheeler TM, et al. Prognostic value of Akt-1 in human prostate cancer: a computerized quantitative assessment with quantum dot technology. Clin Cancer Res. 2009;15(10):3568–73.

    Article  PubMed  CAS  Google Scholar 

  23. Schlomm T, Kirstein P, Iwers L, et al. Clinical significance of epidermal growth factor receptor protein overexpression and gene copy number gains in prostate cancer. Clin Cancer Res. 2007;13(22 Pt 1):6579–84.

    Article  PubMed  CAS  Google Scholar 

  24. Moul JW, Friedrichs PA, Lance RS, Theune SM, Chang EH. Infrequent RAS oncogene mutations in human prostate cancer. Prostate. 1992;20(4):327–38.

    Article  PubMed  CAS  Google Scholar 

  25. Migita T, Ruiz S, Fornari A, et al. Fatty acid synthase: a metabolic enzyme and candidate oncogene in prostate cancer. J Natl Cancer Inst. 2009;101(7):519–32.

    Article  PubMed  CAS  Google Scholar 

  26. Nguyen PL, Ma J, Chavarro JE, et al. Fatty acid synthase polymorphisms, tumor expression, body mass index, prostate cancer risk, and survival. J Clin Oncol. 2010;28:3958–64.

    Article  PubMed  CAS  Google Scholar 

  27. Varambally S, Dhanasekaran SM, Zhou M, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002;419(6907):624–9.

    Article  PubMed  CAS  Google Scholar 

  28. Lee CT, Capodieci P, Osman I, et al. Overexpression of the cyclin-dependent kinase inhibitor p16 is associated with tumor recurrence in human prostate cancer. Clin Cancer Res. 1999;5(5):977–83.

    PubMed  CAS  Google Scholar 

  29. Aaltomaa S, Lipponen P, Eskelinen M, Ala-Opas M, Kosma VM. Prognostic value and expression of p21(waf1/cip1) protein in prostate cancer. Prostate. 1999;39(1):8–15.

    Article  PubMed  CAS  Google Scholar 

  30. Kuczyk M, Machtens S, Hradil K, et al. Predictive value of decreased p27Kip1 protein expression for the recurrence-free and long-term survival of prostate cancer patients. Br J Cancer. 1999;81(6):1052–8.

    Article  PubMed  CAS  Google Scholar 

  31. Yang G, Ayala G, De Marzo A, et al. Elevated Skp2 protein expression in human prostate cancer: association with loss of the cyclin-dependent kinase inhibitor p27 and PTEN and with reduced recurrence-free survival. Clin Cancer Res. 2002;8(11):3419–26.

    PubMed  CAS  Google Scholar 

  32. Sato K, Qian J, Slezak JM, et al. Clinical significance of alterations of chromosome 8 in high-grade, advanced, nonmetastatic prostate carcinoma. J Natl Cancer Inst. 1999;91(18):1574–80.

    Article  PubMed  CAS  Google Scholar 

  33. Prowatke I, Devens F, Benner A, et al. Expression analysis of imbalanced genes in prostate carcinoma using tissue microarrays. Br J Cancer. 2007;96(1):82–8.

    Article  PubMed  CAS  Google Scholar 

  34. Pomerantz MM, Beckwith CA, Regan MM, et al. Evaluation of the 8q24 prostate cancer risk locus and MYC expression. Cancer Res. 2009;69(13):5568–74.

    Article  PubMed  CAS  Google Scholar 

  35. Fordyce CA, Heaphy CM, Joste NE, Smith AY, Hunt WC, Griffith JK. Association between cancer-free survival and telomere DNA content in prostate tumors. J Urol. 2005;173(2):610–4.

    Article  PubMed  CAS  Google Scholar 

  36. Bauer JJ, Sesterhenn IA, Mostofi KF, McLeod DG, Srivastava S, Moul JW. p53 nuclear protein expression is an independent prognostic marker in clinically localized prostate cancer patients undergoing radical prostatectomy. Clin Cancer Res. 1995;1(11):1295–300.

    PubMed  CAS  Google Scholar 

  37. Concato J, Jain D, Uchio E, Risch H, Li WW, Wells CK. Molecular markers and death from prostate cancer. Ann Intern Med. 2009;150(9):595–603.

    PubMed  Google Scholar 

  38. Bauer JJ, Sesterhenn IA, Mostofi FK, McLeod DG, Srivastava S, Moul JW. Elevated levels of apoptosis regulator proteins p53 and bcl-2 are independent prognostic biomarkers in surgically treated clinically localized prostate cancer. J Urol. 1996;156(4):1511–6.

    Article  PubMed  CAS  Google Scholar 

  39. Scherr DS, Vaughan Jr ED, Wei J, et al. BCL-2 and p53 expression in clinically localized prostate cancer predicts response to external beam radiotherapy. J Urol. 1999;162(1):12–6; discussion 16–7.

    Article  PubMed  CAS  Google Scholar 

  40. Mackey TJ, Borkowski A, Amin P, Jacobs SC, Kyprianou N. bcl-2/bax ratio as a predictive marker for therapeutic response to radiotherapy in patients with prostate cancer. Urology. 1998;52(6):1085–90.

    Article  PubMed  CAS  Google Scholar 

  41. Vergis R, Corbishley CM, Norman AR, et al. Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer and outcome of radical treatment: a retrospective analysis of two randomised radiotherapy trials and one surgical cohort study. Lancet Oncol. 2008;9(4):342–51.

    Article  PubMed  Google Scholar 

  42. Li R, Younes M, Wheeler TM, et al. Expression of vascular endothelial growth factor receptor-3 (VEGFR-3) in human prostate. Prostate. 2004;58(2):193–9.

    Article  PubMed  CAS  Google Scholar 

  43. Richmond PJ, Karayiannakis AJ, Nagafuchi A, Kaisary AV, Pignatelli M. Aberrant E-cadherin and alpha-catenin expression in prostate cancer: correlation with patient survival. Cancer Res. 1997;57(15):3189–93.

    PubMed  CAS  Google Scholar 

  44. Wikström P, Stattin P, Franck-Lissbrant I, Damber JE, Bergh A. Transforming growth factor beta1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer. Prostate. 1998;37(1):19–29.

    Article  PubMed  Google Scholar 

  45. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.

    Article  PubMed  CAS  Google Scholar 

  46. Kan Z, Jaiswal BS, Stinson J, et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature. 2010;466(7308):869–73.

    Article  PubMed  CAS  Google Scholar 

  47. Mucci L, Powolny A, Giovannucci E, et al. Prospective study of prostate tumor angiogenesis and cancer-specific mortality in the health professionals follow-up study. J Clin Oncol. 2009;27:5627–33.

    Article  PubMed  Google Scholar 

  48. Pantel K, Brakenhoff RH, Brandt B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer. 2008;8(5):329–40.

    Article  PubMed  CAS  Google Scholar 

  49. Riethdorf S, Wikman H, Pantel K. Review: biological relevance of disseminated tumor cells in cancer patients. Int J Cancer. 2008;123(9):1991–2006.

    Article  PubMed  CAS  Google Scholar 

  50. Panteleakou Z, Lembessis P, Sourla A, et al. Detection of circulating tumor cells in prostate cancer patients: methodological pitfalls and clinical relevance. Mol Med (Cambridge, Mass). 2009;15(3–4):101–14.

    CAS  Google Scholar 

  51. Wood Jr DP, Banerjee M. Presence of circulating prostate cells in the bone marrow of patients undergoing radical prostatectomy is predictive of disease-free survival. J Clin Oncol. 1997;15(12):3451–7.

    PubMed  Google Scholar 

  52. Berg A, Berner A, Lilleby W, et al. Impact of disseminated tumor cells in bone marrow at diagnosis in patients with nonmetastatic prostate cancer treated by definitive radiotherapy. Int J Cancer. 2007;120(8):1603–9.

    Article  PubMed  CAS  Google Scholar 

  53. Kollermann J, Weikert S, Schostak M, et al. Prognostic significance of disseminated tumor cells in the bone marrow of prostate cancer patients treated with neoadjuvant hormone treatment. J Clin Oncol. 2008;26(30):4928–33.

    Article  PubMed  Google Scholar 

  54. Kantoff PW, Halabi S, Farmer DA, Hayes DF, Vogelzang NA, Small EJ. Prognostic significance of reverse transcriptase polymerase chain reaction for prostate-specific antigen in men with hormone-refractory prostate cancer. J Clin Oncol. 2001;19(12):3025–8.

    PubMed  CAS  Google Scholar 

  55. Ross RW, Manola J, Hennessy K, et al. Prognostic significance of baseline reverse transcriptase-PCR for prostate-specific antigen in men with hormone-refractory prostate cancer treated with chemotherapy. Clin Cancer Res. 2005;11(14):5195–8.

    Article  PubMed  CAS  Google Scholar 

  56. Danila DC, Heller G, Gignac GA, et al. Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res. 2007;13(23):7053–8.

    Article  PubMed  CAS  Google Scholar 

  57. de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14(19):6302–9.

    Article  PubMed  Google Scholar 

  58. Goodman Jr OB, Fink LM, Symanowski JT, et al. Circulating tumor cells in patients with castration-resistant prostate cancer baseline values and correlation with prognostic factors. Cancer Epidemiol Biomarkers Prev. 2009;18(6):1904–13.

    Article  PubMed  CAS  Google Scholar 

  59. Olmos D, Arkenau HT, Ang JE, et al. Circulating tumour cell (CTC) counts as intermediate end points in castration-resistant prostate cancer (CRPC): a single-centre experience. Ann Oncol. 2009;20(1):27–33.

    Article  PubMed  CAS  Google Scholar 

  60. Davis JW, Nakanishi H, Kumar VS, et al. Circulating tumor cells in peripheral blood samples from patients with increased serum prostate specific antigen: initial results in early prostate cancer. J Urol. 2008;179(6):2187–91; discussion 2191.

    Article  PubMed  Google Scholar 

  61. Attard G, Swennenhuis JF, Olmos D, et al. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res. 2009;69(7):2912–8.

    Article  PubMed  CAS  Google Scholar 

  62. Leversha MA, Han J, Asgari Z, et al. Fluorescence in situ hybridization analysis of circulating tumor cells in metastatic prostate cancer. Clin Cancer Res. 2009;15(6):2091–7.

    Article  PubMed  CAS  Google Scholar 

  63. Holcomb IN, Grove DI, Kinnunen M, et al. Genomic alterations indicate tumor origin and varied metastatic potential of disseminated cells from prostate cancer patients. Cancer Res. 2008;68(14):5599–608.

    Article  PubMed  CAS  Google Scholar 

  64. Maheswaran S, Sequist LV, Nagrath S, et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med. 2008;359(4):366–77.

    Article  PubMed  CAS  Google Scholar 

  65. Bussemakers MJ, van Bokhoven A, Verhaegh GW, et al. DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res. 1999;59(23):5975–9.

    PubMed  CAS  Google Scholar 

  66. de Kok JB, Verhaegh GW, Roelofs RW, et al. DD3(PCA3), a very sensitive and specific marker to detect prostate tumors. Cancer Res. 2002;62(9):2695–8.

    PubMed  Google Scholar 

  67. Landers KA, Burger MJ, Tebay MA, et al. Use of multiple biomarkers for a molecular diagnosis of prostate cancer. Int J Cancer. 2005;114(6):950–6.

    Article  PubMed  CAS  Google Scholar 

  68. Vlaeminck-Guillem V, Ruffion A, Andre J, Devonec M, Paparel P. Urinary prostate cancer 3 test: toward the age of reason? Urology. 2010;75:447–53. Epub 2009 Jul 8.

    Article  PubMed  Google Scholar 

  69. Whitman EJ, Groskopf J, Ali A, et al. PCA3 score before radical prostatectomy predicts extracapsular extension and tumor volume. J Urol. 2008;180(5):1975–8; discussion 1978–79.

    Article  PubMed  Google Scholar 

  70. Laxman B, Tomlins SA, Mehra R, et al. Noninvasive detection of TMPRSS2:ERG fusion transcripts in the urine of men with prostate cancer. Neoplasia. 2006;8(10):885–8.

    Article  PubMed  CAS  Google Scholar 

  71. Rostad K, Hellwinkel OJ, Haukaas SA, et al. TMPRSS2:ERG fusion transcripts in urine from prostate cancer patients correlate with a less favorable prognosis. APMIS. 2009;117(8):575–82.

    Article  PubMed  CAS  Google Scholar 

  72. Hessels D, Smit FP, Verhaegh GW, Witjes JA, Cornel EB, Schalken JA. Detection of TMPRSS2-ERG fusion transcripts and prostate cancer antigen 3 in urinary sediments may improve diagnosis of prostate cancer. Clin Cancer Res. 2007;13(17):5103–8.

    Article  PubMed  CAS  Google Scholar 

  73. Laxman B, Morris DS, Yu J, et al. A first-generation multiplex biomarker analysis of urine for the early detection of prostate cancer. Cancer Res. 2008;68(3):645–9.

    Article  PubMed  CAS  Google Scholar 

  74. Haese A, Graefen M, Becker C, et al. The role of human glandular kallikrein 2 for prediction of pathologically organ confined prostate cancer. Prostate. 2003;54(3):181–6.

    Article  PubMed  CAS  Google Scholar 

  75. Karazanashvili G, Abrahamsson PA. Prostate specific antigen and human glandular kallikrein 2 in early detection of prostate cancer. J Urol. 2003;169(2):445–57.

    Article  PubMed  CAS  Google Scholar 

  76. Shariat SF, Shalev M, Menesses-Diaz A, et al. Preoperative plasma levels of transforming growth factor beta(1) (TGF-beta(1)) strongly predict progression in patients undergoing radical prostatectomy. J Clin Oncol. 2001;19(11):2856–64.

    PubMed  CAS  Google Scholar 

  77. Kattan MW, Shariat SF, Andrews B, et al. The addition of interleukin-6 soluble receptor and transforming growth factor beta1 improves a preoperative nomogram for predicting biochemical progression in patients with clinically localized prostate cancer. J Clin Oncol. 2003;21(19):3573–9.

    Article  PubMed  CAS  Google Scholar 

  78. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst. 2005;97(16):1180–4.

    Article  PubMed  CAS  Google Scholar 

  79. Liu J, Lau SK, Varma VA, et al. Molecular mapping of tumor heterogeneity on clinical tissue specimens with multiplexed quantum dots. ACS Nano. 2010;4(5):2755–65.

    Article  PubMed  CAS  Google Scholar 

  80. Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22.

    Article  PubMed  CAS  Google Scholar 

  81. Cuzick J, Swanson GP, 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.

    Article  PubMed  CAS  Google Scholar 

  82. Ding Z, Wu CJ, Chu GC, et al. SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature. 2011;470:269–73.

    Article  PubMed  CAS  Google Scholar 

  83. Penney KL, Sinnott JA, Fall K, et al. mRNA expression signature of Gleason grade predicts lethal prostate cancer. J Clin Oncol. 2011;29:2391–6.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, 75 Francis Street, ASB-IL2, Boston, MA, 02115, USA

    Neil E. Martin M.D., MPH

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  1. Neil E. Martin M.D., MPH
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Correspondence to Neil E. Martin M.D., MPH .

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  1. New York Presbyterian Hospital, Brady Urologic Health Center, Weill Cornell Medical Center, East 68th Street 525, New York, 10021, New York, USA

    Ashutosh Tewari

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Martin, N.E. (2013). Molecular Risk Profiling. In: Tewari, A. (eds) Prostate Cancer: A Comprehensive Perspective. Springer, London. https://doi.org/10.1007/978-1-4471-2864-9_18

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