Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The complexity of prostate cancer: genomic alterations and heterogeneity

Abstract

Although prostate cancer is the most common malignancy to affect men in the Western world, the molecular mechanisms underlying its development and progression remain poorly understood. Like all cancers, prostate cancer is a genetic disease that is characterized by multiple genomic alterations, including point mutations, microsatellite variations, and chromosomal alterations such as translocations, insertions, duplications, and deletions. In prostate cancer, but not other carcinomas, these chromosome alterations result in a high frequency of gene fusion events. The development and application of novel high-resolution technologies has significantly accelerated the detection of genomic alterations, revealing the complex nature and heterogeneity of the disease. The clinical heterogeneity of prostate cancer can be partly explained by this underlying genetic heterogeneity, which has been observed between patients from different geographical and ethnic populations, different individuals within these populations, different tumour foci within the same patient, and different cells within the same tumour focus. The highly heterogeneous nature of prostate cancer provides a real challenge for clinical disease management and a detailed understanding of the genetic alterations in all cells, including small subpopulations, would be highly advantageous.

Key Points

  • Prostate cancer is the most common malignancy reported in Western men; however, despite extensive investigation, the molecular mechanisms underlying its development and progression are still poorly understood

  • Like most cancers, prostate cancer is characterized by multiple genomic alterations, including point mutations, microsatellite sequence changes, and chromosomal rearrangements (such as translocations, insertions, duplications, and deletions)

  • Prostate cancer is associated with high levels of interpatient heterogeneity (including geographical and ethnic heterogeneity) and intrapatient heterogeneity (for example, interfocal and intrafocal heterogeneity)

  • Given its heterogeneity, clinical management of prostate cancer is challenging and requires a detailed understanding of the genetic alterations that occur in all cells, including small subpopulations

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Intrafocal heterogeneity at the PTEN locus.

References

  1. Ruijter, E. T., van de Kaa, C. A., Schalken, J. A., Debruyne, F. M. & Ruiter, D. J. Histological grade heterogeneity in multifocal prostate cancer: Biological and clinical implications. J. Pathol. 180, 295–299 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Qian, J., Jenkins, R. B. & Bostwick, D. G. Chromosomal anomalies in atypical adenomatous hyperplasia and carcinoma of the prostate using fluorescence in situ hybridization. Urology 46, 837–842 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. Miller, G. J. & Cygan, J. M. Morphology of prostate cancer: the effects of multifocality on histological grade, tumor volume and capsule penetration. J. Urol. 152, 1709–1713 (1994).

    Article  CAS  PubMed  Google Scholar 

  4. Greene, D. R., Wheeler, T. M., Egawa, S., Dunn, J. K. & Scardino, P. T. A comparison of the morphological features of cancer arising in the transition zone and in the peripheral zone of the prostate. J. Urol. 146, 1069–1076 (1991).

    Article  CAS  PubMed  Google Scholar 

  5. Villers, A., McNeal, J. E., Freiha, F. S. & Stamey, T. A. Multiple cancers in the prostate. Morphologic features of clinically recognized versus incidental tumors. Cancer 70, 2313–2318 (1992).

    Article  CAS  PubMed  Google Scholar 

  6. Arora, R. et al. Heterogeneity of Gleason grade in multifocal adenocarcinoma of the prostate. Cancer 100, 2362–2366 (2004).

    Article  PubMed  Google Scholar 

  7. Stamatiou, K. N. et al. The phenomenon of multifocality does not affect the biologic behavior of histologic prostate carcinoma. Med. Sci. Monit. 15, BR61–BR63 (2009).

    PubMed  Google Scholar 

  8. Humphrey, P. A. Gleason grading and prognostic factors in carcinoma of the prostate. Mod. Pathol. 17, 292–306 (2004).

    Article  PubMed  Google Scholar 

  9. Carter, B. S., Beaty, T. H., Steinberg, G. D., Childs, B. & Walsh, P. C. Mendelian inheritance of familial prostate cancer. Proc. Natl Acad. Sci. USA 89, 3367–3371 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Edwards, S. M. & Eeles, R. A. Unravelling the genetics of prostate cancer. Am. J. Med. Genet. C Semin. Med. Genet. 129C, 65–73 (2004).

    Article  PubMed  Google Scholar 

  11. Gudmundsson, J. et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat. Genet. 39, 631–637 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Yeager, M. et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat. Genet. 39, 645–649 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Gudmundsson, J. et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat. Genet. 39, 977–983 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Gudmundsson, J. et al. Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer. Nat. Genet. 40, 281–283 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Eeles, R. A. et al. Multiple newly identified loci associated with prostate cancer susceptibility. Nat. Genet. 40, 316–321 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Thomas, G. et al. Multiple loci identified in a genome-wide association study of prostate cancer. Nat. Genet. 40, 310–315 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Gudmundsson, J. et al. Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility. Nat. Genet. 41, 1122–1126 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Eeles, R. A. et al. Identification of seven new prostate cancer susceptibility loci through a genome-wide association study. Nat. Genet. 41, 1116–1121 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yeager, M. et al. Identification of a new prostate cancer susceptibility locus on chromosome 8q24. Nat. Genet. 41, 1055–1057 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Al Olama, A. A. et al. Multiple loci on 8q24 associated with prostate cancer susceptibility. Nat. Genet. 41, 1058–1060 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Easton, D. F. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Amundadottir, L. T. et al. A common variant associated with prostate cancer in European and African populations. Nat. Genet. 38, 652–658 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Haiman, C. A. et al. Multiple regions within 8q24 independently affect risk for prostate cancer. Nat. Genet. 39, 638–644 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Takata, R. et al. Genome-wide association study identifies five new susceptibility loci for prostate cancer in the Japanese population. Nat. Genet. 42, 751–754 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Mao, X., Young, B. D. & Lu, Y. J. The application of single nucleotide polymorphism microarrays in cancer research. Curr. Genom. 8, 219–228 (2007).

    Article  CAS  Google Scholar 

  26. Emanuel, B. S. & Saitta, S. C. From microscopes to microarrays: dissecting recurrent chromosomal rearrangements. Nat. Rev. Genet. 8, 869–883 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Boyd, L. K., Mao, X. & Lu, Y.-J. Use of SNPs in cancer predisposition analysis, diagnosis and prognosis: tools and prospects. Expert Opin.Med. Diagnost. 3, 313–326 (2009).

    Article  CAS  Google Scholar 

  28. Smith, J. R. et al. Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 274, 1371–1374 (1996).

    Article  CAS  PubMed  Google Scholar 

  29. Carpten, J. et al. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nat. Genet. 30, 181–184 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Xu, J. Combined analysis of hereditary prostate cancer linkage to 1q24–25: results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics. Am. J. Hum. Genet. 66, 945–957 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Berthon, P. et al. Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2–43. Am. J. Hum. Genet. 62, 1416–1424 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gibbs, M. et al. Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36. Am. J. Hum. Genet. 64, 776–787 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tavtigian, S. V. et al. A candidate prostate cancer susceptibility gene at chromosome 17p. Nat. Genet. 27, 172–180 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Berry, R. et al. Evidence for a prostate cancer-susceptibility locus on chromosome 20. Am. J. Hum. Genet. 67, 82–91 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Xu, J. et al. Evidence for a prostate cancer susceptibility locus on the X chromosome. Nat. Genet. 20, 175–179 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Schaid, D. J. et al. Comparison of microsatellites versus single-nucleotide polymorphisms in a genome linkage screen for prostate cancer-susceptibility loci. Am. J. Hum. Genet. 75, 948–965 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Easton, D. F., Schaid, D. J., Whittemore, A. S. & Isaacs, W. J. Where are the prostate cancer genes?—A summary of eight genome wide searches. Prostate 57, 261–269 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Schaid, D. J. The complex genetic epidemiology of prostate cancer. Hum. Mol. Genet. 13, R103–R121 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Xu, J. et al. Evaluation of linkage and association of HPC2/ELAC2 in patients with familial or sporadic prostate cancer. Am. J. Hum. Genet. 68, 901–911 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Xu, J. et al. Genome-wide scan for prostate cancer susceptibility genes in the Johns Hopkins hereditary prostate cancer families. Prostate 57, 320–325 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Wiklund, F. et al. Genome-wide scan of Swedish families with hereditary prostate cancer: suggestive evidence of linkage at 5q11.2 and 19p13.3. Prostate 57, 290–297 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Schleutker, J. et al. Genome-wide scan for linkage in finnish hereditary prostate cancer (HPC) families identifies novel susceptibility loci at 11q14 and 3p25–26. Prostate 57, 280–289 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Lange, E. M. et al. Genome-wide scan for prostate cancer susceptibility genes using families from the University of Michigan prostate cancer genetics project finds evidence for linkage on chromosome 17 near BRCA1. Prostate 57, 326–334 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Gillanders, E. M. et al. Combined genome-wide scan for prostate cancer susceptibility genes. J. Natl Cancer Inst. 96, 1240–1247 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Ewing, C. M. et al. Germline mutations in HOXB13 and prostate-cancer risk. N. Engl. J. Med. 366, 141–149 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Suarez, B. K. et al. Replication linkage study for prostate cancer susceptibility genes. Prostate 45, 106–114 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Edwards, S. et al. Results of a genome-wide linkage analysis in prostate cancer families ascertained through the ACTANE consortium. Prostate 57, 270–279 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Janer, M. et al. Genomic scan of 254 hereditary prostate cancer families. Prostate 57, 309–319 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Xu, J. et al. Linkage and association studies of prostate cancer susceptibility: evidence for linkage at 8p22–23. Am. J. Hum. Genet. 69, 341–350 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hsieh, C. L. et al. A genome screen of families with multiple cases of prostate cancer: evidence of genetic heterogeneity. Am. J. Hum. Genet. 69, 148–158 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Freedman, M. L. et al. Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc. Natl Acad. Sci. USA 103, 14068–14073 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ahn, J. et al. Prostate cancer predisposition loci and risk of metastatic disease and prostate cancer recurrence. Clin. Cancer Res. 17, 1075–1081 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pomerantz, M. M. et al. Analysis of the 10q11 cancer risk locus implicates MSMB and NCOA4 in human prostate tumorigenesis. PLoS Genet. 6, e1001204 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chang, B. L. et al. Validation of genome-wide prostate cancer associations in men of African descent. Cancer Epidemiol. Biomarkers Prev. 20, 23–32 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Sun, J. et al. Evidence for two independent prostate cancer risk-associated loci in the HNF1B gene at 17q12. Nat. Genet. 40, 1153–1155 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wasserman, N. F., Aneas, I. & Nobrega, M. A. An 8q24 gene desert variant associated with prostate cancer risk confers differential in vivo activity to a MYC enhancer. Genome Res. 20, 1191–1197 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sotelo, J. et al. Long-range enhancers on 8q24 regulate c-Myc. Proc. Natl Acad. Sci. USA 107, 3001–3005 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kote-Jarai, Z. et al. Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript. Hum. Genet. 129, 687–694 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kote-Jarai, Z. et al. Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study. Nat. Genet. 43, 785–791 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang, D. et al. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474, 390–394 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Mao, X. et al. Distinct genomic alterations in prostate cancers in Chinese and Western populations suggest alternative pathways of prostate carcinogenesis. Cancer Res. 70, 5207–5212 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Mhatre, A. N. et al. Reduced transcriptional regulatory competence of the androgen receptor in X-linked spinal and bulbar muscular atrophy. Nat. Genet. 5, 184–188 (1993).

    Article  CAS  PubMed  Google Scholar 

  63. Beilin, J., Ball, E. M., Favaloro, J. M. & Zajac, J. D. Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell lines. J. Mol. Endocrinol. 25, 85–96 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Simanainen, U. et al. Length of the human androgen receptor glutamine tract determines androgen sensitivity in vivo. Mol. Cell Endocrinol. 342, 81–86 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kumar, R. et al. Role of the androgen receptor CAG repeat polymorphism in prostate cancer, and spinal and bulbar muscular atrophy. Life Sci. 88, 565–571 (2011).

    Article  CAS  PubMed  Google Scholar 

  66. Hsing, A. W. et al. Polymorphic CAG and GGN repeat lengths in the androgen receptor gene and prostate cancer risk: a population-based case-control study in China. Cancer Res. 60, 5111–5116 (2000).

    CAS  PubMed  Google Scholar 

  67. Buchanan, G., Irvine, R. A., Coetzee, G. A. & Tilley, W. D. Contribution of the androgen receptor to prostate cancer predisposition and progression. Cancer Metastasis Rev. 20, 207–223 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Gu, M., Dong, X., Zhang, X. & Niu, W. The CAG repeat polymorphism of androgen receptor gene and prostate cancer: a meta-analysis. Mol. Biol. Rep. 39, 2615–2624 (2012).

    Article  CAS  PubMed  Google Scholar 

  69. Hsing, A. W. et al. Polymorphic markers in the SRD5A2 gene and prostate cancer risk: a population-based case-control study. Cancer Epidemiol. Biomarkers Prev. 10, 1077–1082 (2001).

    CAS  PubMed  Google Scholar 

  70. Makridakis, N. M. et al. Association of mis-sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles, USA. Lancet 354, 975–978 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Lindstrom, S. et al. Systematic replication study of reported genetic associations in prostate cancer: Strong support for genetic variation in the androgen pathway. Prostate 66, 1729–1743 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Ntais, C., Polycarpou, A. & Ioannidis, J. P. Association of the CYP17 gene polymorphism with the risk of prostate cancer: a meta-analysis. Cancer Epidemiol. Biomarkers Prev. 12, 120–126 (2003).

    CAS  PubMed  Google Scholar 

  73. Mononen, N. & Schleutker, J. Polymorphisms in genes involved in androgen pathways as risk factors for prostate cancer. J. Urol. 181, 1541–1549 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Ross, R. K. et al. Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility. Cancer Res. 58, 4497–4504 (1998).

    CAS  PubMed  Google Scholar 

  75. Ntais, C., Polycarpou, A. & Ioannidis, J. P. SRD5A2 gene polymorphisms and the risk of prostate cancer: a meta-analysis. Cancer Epidemiol. Biomarkers Prev. 12, 618–624 (2003).

    CAS  PubMed  Google Scholar 

  76. Dong, J. T. Prevalent mutations in prostate cancer. J. Cell Biochem. 97, 433–447 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Grignon, D. J. et al. p53 status and prognosis of locally advanced prostatic adenocarcinoma: a study based on RTOG 8610. J. Natl Cancer Inst. 89, 158–165 (1997).

    Article  CAS  PubMed  Google Scholar 

  78. Quinn, D. I. et al. Prognostic significance of p53 nuclear accumulation in localized prostate cancer treated with radical prostatectomy. Cancer Res. 60, 1585–1594 (2000).

    CAS  PubMed  Google Scholar 

  79. Carter, B. S., Epstein, J. I. & Isaacs, W. B. ras gene mutations in human prostate cancer. Cancer Res. 50, 6830–6832 (1990).

    CAS  PubMed  Google Scholar 

  80. Capella, G., Cronauer-Mitra, S., Pienado, M. A. & Perucho, M. Frequency and spectrum of mutations at codons 12 and 13 of the c-K-ras gene in human tumors. Environ. Health Perspect. 93, 125–131 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Gumerlock, P. H., Poonamallee, U. R., Meyers, F. J. & deVere White, R. W. Activated ras alleles in human carcinoma of the prostate are rare. Cancer Res. 51, 1632–1637 (1991).

    CAS  PubMed  Google Scholar 

  82. Konishi, N. et al. K-ras activation and ras p21 expression in latent prostatic carcinoma in Japanese men. Cancer 69, 2293–2299 (1992).

    Article  CAS  PubMed  Google Scholar 

  83. Cho, N. Y. et al. BRAF and KRAS mutations in prostatic adenocarcinoma. Int. J. Cancer 119, 1858–1862 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Zheng, L. et al. Unique substitution of CHEK2 and TP53 mutations implicated in primary prostate tumors and cancer cell lines. Hum. Mutat. 27, 1062–1063 (2006).

    Article  PubMed  Google Scholar 

  85. Wu, X., Dong, X., Liu, W. & Chen, J. Characterization of CHEK2 mutations in prostate cancer. Hum. Mutat. 27, 742–747 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Huusko, P. et al. Nonsense-mediated decay microarray analysis identifies mutations of EPHB2 in human prostate cancer. Nat. Genet. 36, 979–983 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Casey, G. et al. RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases. Nat. Genet. 32, 581–583 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Urisman, A. et al. Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog. 2, e25 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Douglas, D. A. et al. Novel mutations of epidermal growth factor receptor in localized prostate cancer. Front. Biosci. 11, 2518–2525 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Wong, O. G. et al. Plexin-B1 mutations in prostate cancer. Proc. Natl Acad. Sci. USA 104, 19040–19045 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sun, X. et al. Frequent somatic mutations of the transcription factor ATBF1 in human prostate cancer. Nat. Genet. 37, 407–412 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Chen, C. et al. Deletion, mutation, and loss of expression of KLF6 in human prostate cancer. Am. J. Pathol. 162, 1349–1354 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Berger, M. F. et al. The genomic complexity of primary human prostate cancer. Nature 470, 214–220 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kan, Z. et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466, 869–873 (2010).

    Article  CAS  PubMed  Google Scholar 

  95. Barbieri, C. E. et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat. Genet. 44, 685–689 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Grasso, C. S. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487, 239–243 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kumar, A. et al. Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers. Proc. Natl Acad. Sci. USA 108, 17087–17092 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Taplin, M. E. et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N. Engl. J. Med. 332, 1393–1398 (1995).

    Article  CAS  PubMed  Google Scholar 

  99. Marcelli, M. et al. Androgen receptor mutations in prostate cancer. Cancer Res. 60, 944–949 (2000).

    CAS  PubMed  Google Scholar 

  100. Feldman, B. J. & Feldman, D. The development of androgen-independent prostate cancer. Nat. Rev. Cancer 1, 34–45 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. Koivisto, P. et al. Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res. 57, 314–319 (1997).

    CAS  PubMed  Google Scholar 

  102. Gregory, C. W. et al. A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res. 61, 4315–4319 (2001).

    CAS  PubMed  Google Scholar 

  103. Linja, M. J. et al. Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res. 61, 3550–3555 (2001).

    CAS  PubMed  Google Scholar 

  104. Gottlieb, B., Beitel, L. K., Wu, J. H. & Trifiro, M. The androgen receptor gene mutations database (ARDB): 2004 update. Hum. Mutat. 23, 527–533 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Veldscholte, J. et al. Unusual specificity of the androgen receptor in the human prostate tumor cell line LNCaP: high affinity for progestagenic and estrogenic steroids. Biochim. Biophys. Acta 1052, 187–194 (1990).

    Article  CAS  PubMed  Google Scholar 

  106. Taplin, M. E. et al. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res. 59, 2511–2515 (1999).

    CAS  PubMed  Google Scholar 

  107. Nupponen, N. N. & Visakorpi, T. Molecular cytogenetics of prostate cancer. Microsc. Res. Tech. 51, 456–463 (2000).

    Article  CAS  PubMed  Google Scholar 

  108. Dong, J. T. Chromosomal deletions and tumor suppressor genes in prostate cancer. Cancer Metastasis Rev. 20, 173–193 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Narla, G. et al. KLF6, a candidate tumor suppressor gene mutated in prostate cancer. Science 294, 2563–2566 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Clark, J. et al. Genome-wide screening for complete genetic loss in prostate cancer by comparative hybridization onto cDNA microarrays. Oncogene 22, 1247–1252 (2003).

    Article  CAS  PubMed  Google Scholar 

  111. Paris, P. L. et al. Whole genome scanning identifies genotypes associated with recurrence and metastasis in prostate tumors. Hum. Mol. Genet. 13, 1303–1313 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Liu, W. et al. Homozygous deletions and recurrent amplifications implicate new genes involved in prostate cancer. Neoplasia 10, 897–907 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Taylor, B. S. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11–22 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Futreal, P. A. et al. A census of human cancer genes. Nat. Rev. Cancer 4, 177–183 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Greaves, M. F. & Wiemels, J. Origins of chromosome translocations in childhood leukaemia. Nat. Rev. Cancer 3, 639–649 (2003).

    Article  CAS  PubMed  Google Scholar 

  116. Mitelman, F., Johansson, B. & Mertens, F. The impact of translocations and gene fusions on cancer causation. Nat. Rev. Cancer 7, 233–245 (2007).

    Article  CAS  PubMed  Google Scholar 

  117. Veronese, M. L., Bullrich, F., Negrini, M. & Croce, C. M. The t(6;16)(p21;q22) chromosome translocation in the LNCaP prostate carcinoma cell line results in a tpc/hpr fusion gene. Cancer Res. 56, 728–732 (1996).

    CAS  PubMed  Google Scholar 

  118. Edwards, P. A. Fusion genes and chromosome translocations in the common epithelial cancers. J. Pathol. 220, 244–254 (2010).

    CAS  PubMed  Google Scholar 

  119. Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Soda, M. et al. Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer. Nature 448, 561–566 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. Nowell, P. C. & Hungerford, D. A. Chromosome studies on normal and leukemic human leukocytes. J. Natl Cancer Inst. 25, 85–109 (1960).

    CAS  PubMed  Google Scholar 

  122. Mehra, R. et al. Comprehensive assessment of TMPRSS2 and ETS family gene aberrations in clinically localized prostate cancer. Mod. Pathol. 20, 538–544 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Lapointe, J. et al. A variant TMPRSS2 isoform and ERG fusion product in prostate cancer with implications for molecular diagnosis. Mod. Pathol. 20, 467–473 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Winnes, M., Lissbrant, E., Damber, J. E. & Stenman, G. Molecular genetic analyses of the TMPRSS2-ERG and TMPRSS2-ETV1 gene fusions in 50 cases of prostate cancer. Oncol. Rep. 17, 1033–1036 (2007).

    CAS  PubMed  Google Scholar 

  125. Perner, S. et al. TMPRSS2-ERG fusion prostate cancer: an early molecular event associated with invasion. Am. J. Surg. Pathol. 31, 882–888 (2007).

    Article  PubMed  Google Scholar 

  126. Nam, R. K. et al. Expression of TMPRSS2:ERG gene fusion in prostate cancer cells is an important prognostic factor for cancer progression. Cancer Biol. Ther. 6, 40–45 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Demichelis, F. et al. TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene 26, 4596–4599 (2007).

    Article  CAS  PubMed  Google Scholar 

  128. Bott, S. R., Arya, M., Shergill, I. S. & Williamson, M. Molecular changes in prostatic cancer. Surg. Oncol. 14, 91–104 (2005).

    Article  CAS  PubMed  Google Scholar 

  129. Liu, W. et al. Multiple genomic alterations on 21q22 predict various TMPRSS2/ERG fusion transcripts in human prostate cancers. Genes Chromosomes Cancer 46, 972–980 (2007).

    Article  CAS  PubMed  Google Scholar 

  130. Carver, B. S. et al. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat. Genet. 41, 619–624 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Mani, R. S. et al. Induced chromosomal proximity and gene fusions in prostate cancer. Science 326, 1230 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Lin, C. et al. Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer. Cell 139, 1069–1083 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Bastus, N. et al. Androgen-induced TMPRSS2:ERG fusion in non-malignant prostate epithelial cells. Cancer Res. 70, 9544–9548 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Haffner, M. C. et al. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat. Genet. 42, 668–675 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Haffner, M. C. et al. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat. Genet. 42, 668–675 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Lee, K., Chae, J. Y., Kwak, C., Ku, J. H. & Moon, K. C. TMPRSS2-ERG gene fusion and clinicopathologic characteristics of Korean prostate cancer patients. Urology 76, 1268 e7–13 (2010).

    Google Scholar 

  137. Miyagi, Y. et al. ETS family-associated gene fusions in Japanese prostate cancer: analysis of 194 radical prostatectomy samples. Mod. Pathol. 23, 1492–1498 (2010).

    Article  PubMed  Google Scholar 

  138. Magi-Galluzzi, C. et al. TMPRSS2-ERG gene fusion prevalence and class are significantly different in prostate cancer of caucasian, african-american and japanese patients. Prostate 71, 489–497 (2011).

    Article  CAS  PubMed  Google Scholar 

  139. Perner, S. et al. TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res. 66, 8337–8341 (2006).

    Article  CAS  PubMed  Google Scholar 

  140. Paulo, P. et al. FLI1 is a novel ETS transcription factor involved in gene fusions in prostate cancer. Genes Chromosomes Cancer 51, 240–249 (2012).

    Article  CAS  PubMed  Google Scholar 

  141. Tomlins, S. A. et al. TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer. Cancer Res. 66, 3396–3400 (2006).

    Article  CAS  PubMed  Google Scholar 

  142. Pflueger, D. et al. N.-myc downstream regulated gene 1 (NDRG1) is fused to ERG in prostate cancer. Neoplasia 11, 804–811 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Pflueger, D. et al. Discovery of non-ETS gene fusions in human prostate cancer using next-generation RNA sequencing. Genome Res. 21, 56–67 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Palanisamy, N. et al. Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. Nat. Med. 16, 793–798 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Maher, C. A. et al. Chimeric transcript discovery by paired-end transcriptome sequencing. Proc. Natl Acad. Sci. USA 106, 12353–12358 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Ren, G. et al. Identification of frequent BRAF copy number gain and alterations of RAF genes in Chinese prostate cancer. Genes Chromosomes Cancer 51, 1014–1023 (2012).

    Article  CAS  PubMed  Google Scholar 

  147. Mao, X. et al. Chromosome rearrangement associated inactivation of tumour suppressor genes in prostate cancer. Am. J. Cancer Res. 1, 604–617 (2011).

    PubMed  PubMed Central  Google Scholar 

  148. Gronberg, H. Prostate cancer epidemiology. Lancet 361, 859–864 (2003).

    Article  PubMed  Google Scholar 

  149. Oishi, K., Yoshida, O. & Schroeder, F. H. The geography of prostate cancer and its treatment in Japan. Cancer Surv. 23, 267–280 (1995).

    CAS  PubMed  Google Scholar 

  150. Mehra, R. et al. Heterogeneity of TMPRSS2 gene rearrangements in multifocal prostate adenocarcinoma: molecular evidence for an independent group of diseases. Cancer Res. 67, 7991–7995 (2007).

    Article  CAS  PubMed  Google Scholar 

  151. Bostwick, D. G. et al. Independent origin of multiple foci of prostatic intraepithelial neoplasia: comparison with matched foci of prostate carcinoma. Cancer 83, 1995–2002 (1998).

    Article  CAS  PubMed  Google Scholar 

  152. Cheng, L. et al. Evidence of independent origin of multiple tumors from patients with prostate cancer. J. Natl Cancer Inst. 90, 233–237 (1998).

    Article  CAS  PubMed  Google Scholar 

  153. Mao, X. et al. Rapid high-resolution karyotyping with precise identification of chromosome breakpoints. Genes Chromosomes Cancer 46, 675–683 (2007).

    Article  CAS  PubMed  Google Scholar 

  154. Boyd, L. K. et al. High-resolution genome-wide copy-number analysis suggests a monoclonal origin of multifocal prostate cancer. Genes Chromosomes Cancer 51, 579–589 (2012).

    Article  CAS  PubMed  Google Scholar 

  155. Liu, W. et al. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat. Med. 15, 559–565 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Barry, M., Perner, S., Demichelis, F. & Rubin, M. A. TMPRSS2-ERG fusion heterogeneity in multifocal prostate cancer: clinical and biologic implications. Urology 70, 630–633 (2007).

    Article  PubMed  Google Scholar 

  157. Suzuki, H. et al. Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues. Cancer Res. 58, 204–209 (1998).

    CAS  PubMed  Google Scholar 

  158. Svensson, M. A. et al. Testing mutual exclusivity of ETS rearranged prostate cancer. Lab. Invest. 91, 404–412 (2011).

    Article  CAS  PubMed  Google Scholar 

  159. Magi-Galluzzi, C. et al. Heterogeneity of androgen receptor content in advanced prostate cancer. Mod. Pathol. 10, 839–845 (1997).

    CAS  PubMed  Google Scholar 

  160. Penney, K. L. et al. Evaluation of 8q24 and 17q risk loci and prostate cancer mortality. Clin. Cancer Res. 15, 3223–3230 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Salinas, C. A. et al. Clinical utility of five genetic variants for predicting prostate cancer risk and mortality. Prostate 69, 363–372 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Wiklund, F. E. et al. Established prostate cancer susceptibility variants are not associated with disease outcome. Cancer Epidemiol. Biomarkers Prev. 18, 1659–1662 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Gallagher, D. J. et al. Susceptibility loci associated with prostate cancer progression and mortality. Clin. Cancer Res. 16, 2819–2832 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Kader, A. K. et al. Individual and cumulative effect of prostate cancer risk-associated variants on clinicopathologic variables in 5,895 prostate cancer patients. Prostate 69, 1195–1205 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Xu, J. et al. Association of prostate cancer risk variants with clinicopathologic characteristics of the disease. Clin. Cancer Res. 14, 5819–5824 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Zheng, S. L. et al. Cumulative association of five genetic variants with prostate cancer. N. Engl. J. Med. 358, 910–919 (2008).

    Article  CAS  PubMed  Google Scholar 

  167. Attard, G., de Bono, J. S., Clark, J. & Cooper, C. S. Studies of TMPRSS2-ERG gene fusions in diagnostic trans-rectal prostate biopsies. Clin. Cancer Res. 16, 1340 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Cuzick, J. 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. 12, 245–255 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Shan, L. et al. The identification of chromosomal translocation, t(4;6)(q22;q15), in prostate cancer. Prostate Cancer Prostatic Dis. 13, 117–125 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Mao, X. et al. Detection of TMPRSS2:ERG fusion gene in circulating prostate cancer cells. Asian J. Androl. 10, 467–473 (2008).

    Article  CAS  PubMed  Google Scholar 

  171. Attard, G. et al. Characterization of, ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res. 69, 2912–2918 (2009).

    Article  CAS  PubMed  Google Scholar 

  172. Attard, G. et al. Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene 27, 253–263 (2008).

    Article  CAS  PubMed  Google Scholar 

  173. Tomlins, S. A. et al. Urine TMPRSS2:ERG fusion transcript stratifies prostate cancer risk in men with elevated serum PSA. Sci. Transl. Med. 3, 94ra72 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Hessels, D. et al. Detection of TMPRSS2-ERG fusion transcripts and prostate cancer antigen 3 in urinary sediments may improve diagnosis of prostate cancer. Clin. Cancer Res. 13, 5103–5108 (2007).

    Article  CAS  PubMed  Google Scholar 

  175. Hessels, D. & Schalken, J. A. The use of PCA3 in the diagnosis of prostate cancer. Nat. Rev. Urol. 6, 255–261 (2009).

    Article  CAS  PubMed  Google Scholar 

  176. Bussemakers, M. J. et al. DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res. 59, 5975–5979 (1999).

    CAS  PubMed  Google Scholar 

  177. Salami, S. S. et al. Combining urinary detection of TMPRSS2:ERG and PCA3 with serum PSA to predict diagnosis of prostate cancer. Urol. Oncol. http://dx.doi.org/10.1016/j.urolonc.2011.04.001.

  178. Nilsson, J. et al. Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer. Br. J. Cancer 100, 1603–1607 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Berney, D. M. et al. Ki-67 and outcome in clinically localised prostate cancer: analysis of conservatively treated prostate cancer patients from the Trans-Atlantic Prostate Group study. Br. J. Cancer 100, 888–893 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Cuzick, J. et al. Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort. Br. J. Cancer 106, 1095–1099 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Nacusi, L. P. & Tindall, D. J. Targeting 5alpha-reductase for prostate cancer prevention and treatment. Nat. Rev. Urol. 8, 378–384 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364, 1995–2005 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Scher, H. I. et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet 375, 1437–1446 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Tran, C. et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324, 787–790 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Carver, B. S. et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19, 575–586 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Tomlins, S. A. et al. The role of SPINK1 in ETS rearrangement-negative prostate cancers. Cancer Cell 13, 519–528 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Ateeq, B. et al. Therapeutic targeting of SPINK1-positive prostate cancer. Sci. Transl. Med. 3, 72ra17 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Shamash, J. et al. Chlorambucil and lomustine (CL56) in absolute hormone refractory prostate cancer: re-induction of endocrine sensitivity an unexpected finding. Br. J. Cancer 92, 36–40 (2005).

    Article  CAS  PubMed  Google Scholar 

  189. Barbieri, C. E., Demichelis, F. & Rubin, M. A. Molecular genetics of prostate cancer: emerging appreciation of genetic complexity. Histopathology 60, 187–198 (2012).

    Article  PubMed  Google Scholar 

  190. Witte, J. S. et al. Genomewide scan for prostate cancer-aggressiveness loci. Am. J. Hum. Genet. 67, 92–99 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Stanford, J. L. et al. Prostate cancer and genetic susceptibility: a genome scan incorporating disease aggressiveness. Prostate 66, 317–325 (2006).

    Article  CAS  PubMed  Google Scholar 

  192. Neville, P. J. et al. Prostate cancer aggressiveness locus on chromosome 7q32-q33 identified by linkage and allelic imbalance studies. Neoplasia 4, 424–431 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Paiss, T. et al. Linkage of aggressive prostate cancer to chromosome 7q31–33 in German prostate cancer families. Eur. J. Hum. Genet. 11, 17–22 (2003).

    Article  CAS  PubMed  Google Scholar 

  194. Slager, S. L. et al. Confirmation of linkage of prostate cancer aggressiveness with chromosome 19q. Am. J. Hum. Genet. 72, 759–762 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Neville, P. J. et al. Prostate cancer aggressiveness locus on chromosome segment 19q12-q13.1 identified by linkage and allelic imbalance studies. Genes Chromosomes Cancer 36, 332–339 (2003).

    Article  CAS  PubMed  Google Scholar 

  196. Johanneson, B. et al. Family-based association analysis of 42 hereditary prostate cancer families identifies the apolipoprotein L3 region on chromosome 22q12 as a risk locus. Hum. Mol. Genet. 19, 3852–3862 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Camp, N. J., Farnham, J. M. & Cannon-Albright, L. A. Localization of a prostate cancer predisposition gene to an 880-kb region on chromosome 22q12.3 in Utah high-risk pedigrees. Cancer Res. 66, 10205–10212 (2006).

    Article  CAS  PubMed  Google Scholar 

  198. Lindstrom, S. et al. Characterizing associations and SNP-environment interactions for GWAS-identified prostate cancer risk markers--results from BPC3. PLoS ONE 6, e17142 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Alvarado, C. et al. Somatic mosaicism and cancer: a micro-genetic examination into the role of the androgen receptor gene in prostate cancer. Cancer Res. 65, 8514–8518 (2005).

    Article  CAS  PubMed  Google Scholar 

  200. Sircar, K. et al. Androgen receptor CAG repeat length contraction in diseased and non-diseased prostatic tissues. Prostate Cancer Prostatic Dis. 10, 360–368 (2007).

    Article  CAS  PubMed  Google Scholar 

  201. Chang, B. L. et al. Polymorphic GGC repeats in the androgen receptor gene are associated with hereditary and sporadic prostate cancer risk. Hum. Genet. 110, 122–129 (2002).

    Article  CAS  PubMed  Google Scholar 

  202. Mononen, N. 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. 60, 6479–6481 (2000).

    CAS  PubMed  Google Scholar 

  203. Kumazawa, T. et al. Microsatellite polymorphism of steroid hormone synthesis gene CYP11A1 is associated with advanced prostate cancer. Int. J. Cancer 110, 140–144 (2004).

    Article  CAS  PubMed  Google Scholar 

  204. Audet-Walsh, E. et al. SRD5A polymorphisms and biochemical failure after radical prostatectomy. Eur. Urol. 60, 1226–1234 (2011).

    Article  CAS  PubMed  Google Scholar 

  205. Cicek, M. S. et al. Association of prostate cancer risk and aggressiveness to androgen pathway genes: SRD5A2, CYP17, and the AR. Prostate 59, 69–76 (2004).

    Article  CAS  PubMed  Google Scholar 

  206. Makridakis, N. M., Caldas Ferraz, L. F. & Reichardt, J. K. Genomic analysis of cancer tissue reveals that somatic mutations commonly occur in a specific motif. Hum. Mutat. 30, 39–48 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Akalu, A., Dlmajian, D. A., Highshaw, R. A., Nichols, P. W. & Reichardt, J. K. Somatic mutations at the SRD5A2 locus encoding prostatic steroid 5alpha-reductase during prostate cancer progression. J. Urol. 161, 1355–1358 (1999).

    Article  CAS  PubMed  Google Scholar 

  208. Rebbeck, T. R., Jaffe, J. M., Walker, A. H., Wein, A. J. & Malkowicz, S. B. Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J. Natl Cancer Inst. 90, 1225–1229 (1998).

    Article  CAS  PubMed  Google Scholar 

  209. Mononen, N. et al. Profiling genetic variation along the androgen biosynthesis and metabolism pathways implicates several single nucleotide polymorphisms and their combinations as prostate cancer risk factors. Cancer Res. 66, 743–747 (2006).

    Article  CAS  PubMed  Google Scholar 

  210. Suzuki, K. et al. Genetic polymorphisms of estrogen receptor alpha, CYP19, catechol-O-methyltransferase are associated with familial prostate carcinoma risk in a Japanese population. Cancer 98, 1411–1416 (2003).

    Article  CAS  PubMed  Google Scholar 

  211. Chang, B. L. et al. Joint effect of HSD3B1 and HSD3B2 genes is associated with hereditary and sporadic prostate cancer susceptibility. Cancer Res. 62, 1784–1789 (2002).

    CAS  PubMed  Google Scholar 

  212. Berndt, S. I. et al. Variant in sex hormone-binding globulin gene and the risk of prostate cancer. Cancer Epidemiol. Biomarkers Prev. 16, 165–168 (2007).

    Article  CAS  PubMed  Google Scholar 

  213. de Muga, S. et al. Molecular alterations of EGFR and PTEN in prostate cancer: association with high-grade and advanced-stage carcinomas. Mod. Pathol. 23, 703–712 (2010).

    Article  CAS  PubMed  Google Scholar 

  214. Peraldo-Neia, C. et al. Epidermal growth factor receptor (EGFR) mutation analysis, gene expression profiling and EGFR protein expression in primary prostate cancer. BMC Cancer 11, 31 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Sun, X. et al. Genetic alterations in the PI3K pathway in prostate cancer. Anticancer Res. 29, 1739–1743 (2009).

    CAS  PubMed  Google Scholar 

  216. Gray, I. C. et al. Mutation and expression analysis of the putative prostate tumour-suppressor gene PTEN. Br. J. Cancer 78, 1296–1300 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Dong, J. T., Li, C. L., Sipe, T. W. & Frierson, H. F. Jr. Mutations of PTEN/MMAC1 in primary prostate cancers from Chinese patients. Clin. Cancer Res. 7, 304–308 (2001).

    CAS  PubMed  Google Scholar 

  218. Alhopuro, P. et al. Somatic mutation analysis of MYH11 in breast and prostate cancer. BMC Cancer 8, 263 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Meyers, F. J. et al. Very frequent p53 mutations in metastatic prostate carcinoma and in matched primary tumors. Cancer 83, 2534–2539 (1998).

    Article  CAS  PubMed  Google Scholar 

  220. Zheng, P. P., Pang, J. C., Hui, A. B. & Ng, H. K. Comparative genomic hybridization detects losses of chromosomes 22 and 16 as the most common recurrent genetic alterations in primary ependymomas. Cancer Genet. Cytogenet. 122, 18–25 (2000).

    Article  CAS  PubMed  Google Scholar 

  221. Cooney, K. A., Wetzel, J. C., Consolino, C. M. & Wojno, K. J. Identification and characterization of proximal 6q deletions in prostate cancer. Cancer Res. 56, 4150–4153 (1996).

    CAS  PubMed  Google Scholar 

  222. Hughes, C., Murphy, A., Martin, C., Sheils, O. & O'Leary, J. Molecular pathology of prostate cancer. J. Clin. Pathol. 58, 673–684 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Chen, C., Bhalala, H. V., Vessella, R. L. & Dong, J. T. KLF5 is frequently deleted and down-regulated but rarely mutated in prostate cancer. Prostate 55, 81–88 (2003).

    Article  CAS  PubMed  Google Scholar 

  224. Cui, J. et al. Chromosome 7 abnormalities in prostate cancer detected by dual-color fluorescence in situ hybridization. Cancer Genet. Cytogenet. 107, 51–60 (1998).

    Article  CAS  PubMed  Google Scholar 

  225. Han, B. et al. A fluorescence in situ hybridization screen for E26 transformation-specific aberrations: identification of DDX5-ETV4 fusion protein in prostate cancer. Cancer Res. 68, 7629–7637 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Tomlins, S. A. et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 448, 595–599 (2007).

    Article  CAS  PubMed  Google Scholar 

  227. Hermans, K. G. et al. Truncated ETV1, fused to novel tissue-specific genes, and full-length ETV1 in prostate cancer. Cancer Res. 68, 7541–7549 (2008).

    Article  CAS  PubMed  Google Scholar 

  228. Attard, G. et al. Heterogeneity and clinical significance of ETV1 translocations in human prostate cancer. Br. J. Cancer 99, 314–320 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Helgeson, B. E. et al. Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions in prostate cancer. Cancer Res. 68, 73–80 (2008).

    Article  CAS  PubMed  Google Scholar 

  230. Rickman, D. S. et al. SLC45A3-ELK4 is a novel and frequent erythroblast transformation-specific fusion transcript in prostate cancer. Cancer Res. 69, 2734–2738 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

L. Boyd and Y.-J. Lu researched, wrote, discussed, and edited the article. X. Mao contributed towards researching the primary literature.

Corresponding author

Correspondence to Yong-Jie Lu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boyd, L., Mao, X. & Lu, YJ. The complexity of prostate cancer: genomic alterations and heterogeneity. Nat Rev Urol 9, 652–664 (2012). https://doi.org/10.1038/nrurol.2012.185

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrurol.2012.185

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer