Prognostic and predictive biomarkers of prostate cancer

In the era of personalized treatment, oncologists are striving to tailor medical treatment to the characteristics of the individual patient, emphasizing the importance of a continuous search for accurate biomarkers. Prognostic biomarkers reflect the intricate underlying biology that enables cancer to progress. Intratumoural heterogeneity includes genetic, epigenetic and functional heterogeneity. Genetic intratumour heterogeneity is a consequence of clonal evolution and a cause of desease progression. Herewith specific mutations are associated with particular stages of tumour development, correlates with specific histopathological disease stages. Many patients with prostate cancer have disease recurrence after resection of the tumor despite adjuvant therapy, while some patients dont have a relapse despite the absence of treatment. So the reassessment of the current criteria and better prognostic and predictive biomarkers for the selection of patients who might benefit from adjuvant chemotherapy are urgently needed. A prognostic biomarker reflects the natural history of the tumor and provides information on the likely outcome and prognosis, independent of a specific treatment. Predictive biomarkers indicate the sensitivity or resistance of the tumor to a given treatment. Some markers can be both prognostic and predictive. Gene mutations and epigenetic changes that modify the intracellular signaling pathways may be important factors in oncogenesis. In this context, oncogenes, genes-tumor suppressors and miRNAs have attracted attention as potential biomarkers and regulators of oncogenesis and evaluate in clinical trials.

prostate cancer, biomarker, tumoural heterogeneity, oncogene, gene-tumor suppressor, mutation, hypermethylation, microRNA

1. Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65(1):5–29. DOI: 10.3322/caac.21254. PMID: 25559415.

2. Torre L.A., Bray F., Siegel R.L. et al. Global cancer statistics, 2012. CA Cancer J Clin 2015;65(2):87–108. DOI: 10.3322/caac.21262. PMID: 25651787.

3. Saad F., Latour M., Lattouf J.B. et al. Biopsy based proteomic assay predicts risk of biochemical recurrence after radical prostatectomy. J Urol 2017;197(4):1034–40. DOI: 10.1016/j.juro.2016.09.116. PMID: 27725152.

4. Zhang Y., Zhang P., Wan X. et al. Downregulation of long non-coding RNA HCG11 predicts a poor prognosis in prostate cancer. Biomed Pharmacother 2016;83:936–41. DOI: 10.1016/j.biopha.2016.08.013. PMID: 27522256.

5. Attard G., Parker C., Eeles R.A. et al. Prostate cancer. Lancet 2016;387(10013):70–82. DOI: 10.1016/S0140-6736(14)61947-4. PMID: 26074382.

6. Hjelmborg J.B., Scheike T., Holst K. et al. The heritability of prostate cancer in the Nordic Twin Study of Cancer. Cancer Epidemiol Biomarkers Prev 2014;23(11): 2303–10. DOI: 10.1158/1055-9965.EPI-13-0568. PMID: 24812039.

7. Al Olama A.A., Kote-Jarai Z., Berndt S.I. et al. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat Genet 2014;46(10):1103–9. DOI: 10.1038/ng.3094. PMID: 25217961.

8. Eeles R., Goh C., Castro E. et al. The genetic epidemiology of prostate cancer and its clinical implications. Nat Rev Urol 2014;11(1):18–31. DOI: 10.1038/nrurol.2013.266. PMID: 24296704.

9. Li L.C., Hsieh A.C., Ruggero D. et al. Molecular basis of prostate cancer. Ch. 38. The molecular basis of cancer. Eds.: J. Mendelsohn, P.M. Howley, M.A. Israel et al. 4th Edn. Philadelphia: Elsevier, 2015. 888 p.

10. Pritchard C.C., Mateo J., Walsh M.F. et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med 2016;375(5):443–53. DOI: 10.1056/NEJMoa1603144. PMID: 27433846.

11. Genetics of Prostate Cancer. PDQ® Cancer Genetics Editorial Board. Bethesda, MD: NCI. Updated November 30, 2016. Available at: https://www.cancer.gov/types/prostate/hp/prostate-geneticspdq/.

12. Mononen N., Syrjäkoski K., Matikainen M. et al. Two percent of Finnish prostate cancer patients have a germ-line mutation in the hormone-binding domain of the androgen receptor gene. Cancer Res 2000;60(22):6479–81. PMID: 11103816.

13. Zheng S.L., Sun J., Wiklund F. et al. Cumulative association of five genetic variants with prostate cancer. N Engl J Med 2008;358(9):910–9. DOI: 10.1056/NEJMoa075819. PMID: 18953706.

14. DePaolo J.S., Wang Z., Guo J. et al. Acetylation of androgen receptor by ARD1 promotes dissociation from HSP90 complex and prostate tumorigenesis. Oncotarget 2016;7(44):71417–28. DOI: 10.18632/oncotarget.12163. PMID: 27659526.

15. Wadosky K.M., Koochekpour S. Molecular mechanisms underlying resistance to androgen deprivation therapy in prostate cancer. Oncotarget 2016;7(39):64447–70. DOI: 10.18632/oncotarget.10901. PMID: 27487144.

16. Wong N., Major P., Kapoor A. et al. Amplification of MUC1 in prostate cancer metastasis and CRPC development. Oncotarget 2016;7(50):83115–33. DOI: 10.18632/oncotarget.13073. PMID: 27825118.

17. Kumar A., Coleman I., Morrissey C. et al. Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat Med 2016;22(4):369–78. DOI: 10.1038/nm.4053. PMID: 26928463.

18. Wadosky K.M., Koochekpour S. Therapeutic rationales, progresses, failures, and future directions for advanced prostate cancer. Int J Biol Sci 2016;12(4):409–26. DOI: 10.7150/ijbs.14090. PMID: 27019626.

19. Azad A.A., Volik S.V., Wyatt A.W. et al. Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic resistance in castrationresistant prostate cancer. Clin Cancer Res 2015;21(10):2315–24. DOI: 10.1158/1078-0432.CCR-14-2666. PMID: 25712683.

20. Antonarakis E.S., Lu C., Wang H. et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014;371(11):1028–38. DOI: 10.1056/NEJMoa1315815. PMID: 26964769.

21. Hornberg E., Ylitalo E.B., Crnalic S. et al. Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival. PLoS One 2011;6(4):e19059. DOI: 10.1371/journal.pone.0019059. PMID: 21552559.

22. Turner A.R., Feng J., Liu W. et al. Prostate Cancer. Genomic and Personalized Medicine. 2nd Edn. Ch. 63. London: Academic Press, 2012. Pp. 733–741.

23. Haraldsdottir S., Hampel H., Wei L. et al. Prostate cancer incidence in males with Lynch syndrome. Genet Med 2014;16(7):553–7. DOI: 10.1038/gim.2013.193. PMID: 24434690.

24. Robinson D., van Allen E.M., Wu Y.M. et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015;161(5):1215–28. DOI: 10.1016/j.cell.2015.05.001.

25. Ellingson M.S., Hart S.N., Kalari K.R. et al. Exome sequencing reveals frequent deleterious germline variants in cancer susceptibility genes in women with invasive breast cancer undergoing neoadjuvant chemotherapy. Breast Cancer Res Treat 2015;153(2):435–43. DOI: 10.1007/s10549-015-3545-6. PMID: 26296701.

26. Leongamornlert D., Saunders E., Dadaev T. et al. Frequent germline deleterious variants in DNA repair genes in familial prostate cancer cases are associated with advanced disease. Br J Cancer 2014;110(6):1663–72. DOI: 10.1038/bjc.2014.30.

27. Tarish F.L., Schultz N., Tanoglidi A. et al. Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand break repair. Sci Transl Med 2015;7(312):312re11. DOI: 10.1126/scitranslmed.aac5671. PMID: 26537259.

28. Polkinghorn W.R., Parker J.S., Lee M.X. et al. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov 2013;3(11):1245–53. DOI: 10.1158/2159-8290.CD-13-0172. PMID: 24027196.

29. Raison N., Elhage O., Dasgupta P. Getting personal with prostate cancer: DNA-repair defects and olaparib in metastatic prostate cancer. BJU Int 2017;119(1):8–9. DOI: 10.1111/bju.13522. PMID: 27154575.

30. Kpetemey M., Dasgupta S., Rajendiran S. et al. MIEN1, a novel interactor of Annexin A2, promotes tumor cell migration by enhancing AnxA2 cell surface expression. Mol Cancer 2015;14:156. DOI: 10.1186/s12943-015-0428-8. PMID: 26272794.

31. Rajendiran S., Gibbs L.D., van Treuren T. et al. MIEN1 is tightly regulated by SINE Alu methylation in its promoter. Oncotarget 2016;7(40):65307–19. DOI: 10.18632/oncotarget.11675. PMID: 27589566.

32. Zhao S., Geybels M.S., Leonardson A. et al. Epigenome wide tumor DNA methylation profiling identifies novel prognostic biomarkers of metastatic-lethal progression in men with clinically localized prostate cancer. Clin Cancer Res 2017;23(1):311–19. DOI: 10.1158/1078-0432.CCR-16-0549. PMID: 27358489.

33. Geybels M.S., Wright J.L., Bibikova M. et al. Epigenetic signature of Gleason score and prostate cancer recurrence after radical prostatectomy. Clin Epigenetics 2016;8:97. DOI: 10.1186/s13148-016-0260-z. PMID: 27651837.

34. Epstein J.I., Zelefsky M.J., Sjoberg D.D. et al. A contemporary prostate cancer grading system: a validated alternative to the Gleason score. Eur Urol 2016;69(3):428–35. DOI: 10.1016/j.eururo.2015.06.046. PMID: 26166626.

35. Singal R., Ramachandran K., Gordian E. et al. Phase I/II study of azacitidine, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxelbased therapy. Clin Genitourin Cancer 2015;13(1):22–31. DOI: 10.1016/j.clgc.2014.07.008. PMID: 25178642.

36. Ayub S.G., Kaul D., Ayub T. Microdissecting the role of microRNAs in the pathogenesis of prostate cancer. Cancer Genet 2015;208(6):289–302. DOI: 10.1016/j.cancergen.2015.02.010. PMID: 26004033.

37. Kojima S., Goto Y., Naya Y. The roles of microRNAs in the progression of castration-resistant prostate cancer. J Hum Genet 2017;62(1):25–31. DOI: 10.1038/jhg.2016.69. PMID: 27278789.

38. Faruq O., Vecchione A. MicroRNA: diagnostic perspective. Front Med 2015;2:51. DOI: 10.3389/fmed.2015.00051. PMID: 26284247.

39. Larne O., Östling P., Haflidadóttir B.S. et al. MiR-183 in prostate cancer cells positively regulates synthesis and serum levels of prostate-specific antigen. Eur Urol 2015;68(4):581–8. DOI: 10.1016/j.eururo.2014.12.025. PMID: 25556023.

40. Chiyomaru T., Yamamura S., Fukuhara S. et al. Genistein inhibits prostate cancer cell growth by targeting miR-34a and oncogenic HOTAIR. PLoS One 2013;8(8):e70372. DOI: 10.1371/journal.pone.0070372. PMID: 23936419.

41. Wang J., Shan M., Liu T. et al. Analysis of TRRAP as a potential molecular marker and therapeutic target for breast cancer. J Breast Cancer 2016;19(1):61–7. DOI: 10.4048/jbc.2016.19.1.61. PMID: 27066097.

42. Gang X., Yang Y., Zhong J. et al. P300 acetyltransferase regulates fatty acid synthase expression, lipid metabolism and prostate cancer growth. Oncotarget 2016;7(12):15135–49. DOI: 10.18632/oncotarget.7715. PMID: 26934656.

43. Blume-Jensen P., Berman D.M., Rimm D.L. et al. Development and clinical validation of an in situ biopsybased multimarker assay for risk stratification in prostate cancer. Clin Cancer Res 2015;21(11):2591–600. DOI: 10.1158/1078-0432.CCR-14-2603. PMID: 25733599.

44. Shvartsur A., Bonavida B. TROP2 and its overexpression in cancers: regulation and clinical/therapeutic implications. Genes Cancer 2015;6(3–4):84–105. DOI: 10.18632/genesandcancer.40. PMID: 26000093.

45. Trerotola M., Ganguly K.K., Fazli L. et al. Trop-2 is up-regulated in invasive prostate cancer and displaces FAK from focal contacts. Oncotarget 2015;6(16):14318–28. DOI: 10.18632/oncotarget.3960. PMID: 26015409.

46. Ju X., Jiao X., Ertel A. et al. v-Src oncogene induces TROP2 proteolytic activation via cyclin D1. Cancer Res 2016;76(22);6723–34. DOI: 10.1158/0008-5472.CAN-15-3327. PMID: 27634768.

47. Lin C.J., Nasr Z., Premsrirut P.K. et al. Targeting synthetic lethal interactions between Myc and the EIF-4F complex impedes tumorigenesis. Cell Rep 2012;1(4):325–33. DOI: 10.1016/j.celrep.2012.02.010. PMID: 22573234.

48. Cencic R., Pelletier J. Hippuristanol – a potent steroid inhibitor of eukaryotic initiation factor 4A. Translation (Austin) 2016;4(1):e1137381. DOI: 10.1080/21690731.2015.1137381. PMID: 27335721.

49. Malina A., Mills J.R., Pelletier J. Emerging therapeutics targeting mRNA translation. Cold Spring Harb Perspect Biol 2012;4(4):a012377. DOI: 10.1101/cshperspect.a012377. PMID: 22474009.

50. Morad S.A., Schmid M., Büchele B. et al. A novel semisynthetic inhibitor of the FRB domain of mammalian target of rapamycin blocks proliferation and triggers apoptosis in chemoresistant prostate cancer cells. Mol Pharmacol 2013;83(2):531–41. DOI: 10.1124/mol.112.081349. PMID: 23208958.

51. Nguyen P.L., Shin H., Yousefi K. et al. Impact of a genomic classifier of metastatic risk on postprostatectomy treatment recommendations by radiation oncologists and urologists. Urology 2015;86(1):35–40. DOI: 10.1016/j.urology.2015.04.004. PMID: 26142578.

52. Ross A.E., Johnson M.H., Yousefi K. et al. Tissue-based genomics augments post-prostatectomy risk stratification in a natural history cohort of intermediateand high-risk men. Eur Urol 2016;69(1):157–65. DOI: 10.1016/j.eururo.2015.05.04. PMID: 26058959.