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.

Recurrent gene fusions in prostate cancer

Key Points

  • Approximately 50% of prostate cancers from serum prostate-specific antigen (PSA)-screened cohorts harbour recurrent gene fusions.

  • The gene fusions in prostate cancer are characterized by 5′ genomic regulatory elements, most commonly controlled by androgen, fused to members of the Ets family of transcription factors.

  • TMPRSS2–ERG is the most common gene fusion, present in about half of all localized prostate cancers analysed. TMPRSS2 also fuses to other Ets family genes such as ETV1, ETV4 and ETV5 in a small percentage of prostate cancers.

  • ETV1, ETV4 and ETV5 have additional 5′ fusion partners that differ in their prostate specificity and response to androgen.

  • Many Ets gene fusion transcript variants have been identified with different 5′ and 3′ partner sequences, probably with prognostic and/or diagnostic implications.

  • Prostate cancers harbouring TMPRSS2–ERG gene fusion display characteristic morphological features of prostate cancers, such as macronucleoli and intraductal tumour spread as well as rare blue-tinged mucin, cribriform growth pattern and signet-ring cell.

  • ERG overexpression imparts invasiveness to prostate cells in vitro and induces plasminogen activation and matrix metalloproteinase pathways.

  • Ets gene fusion-positive and Ets gene fusion-negative prostate cancers have distinct chromosomal aberrations, expression signatures, morphological features and clinical outcomes, suggesting that they are fundamentally different classes of prostate cancer.

  • Sensitive and specific diagnostic tests and targeted therapeutics will affect the detection and management of Ets-positive prostate cancer.

Abstract

The discovery of recurrent gene fusions in a majority of prostate cancers has important clinical and biological implications in the study of common epithelial tumours. Gene fusion and chromosomal rearrangements were previously thought to be primarily the oncogenic mechanism of haematological malignancies and sarcomas. The prostate cancer gene fusions that have been identified thus far are characterized by 5′ genomic regulatory elements, most commonly controlled by androgen, fused to members of the Ets family of transcription factors, leading to the overexpression of oncogenic transcription factors. Ets gene fusions probably define a distinct class of prostate cancer, and this might have a bearing on diagnosis, prognosis and rational therapeutic targeting.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Cytological and molecular techniques used in gene fusion studies.
Figure 2: Anatomy of gene fusions in prostate cancer.
Figure 3: Genesis and progression of gene fusions in prostate cancer.
Figure 4: Role of gene fusions in prostate cancer.
Figure 5: The gamut of gene fusions in prostate cancer.

References

  1. American Cancer Society: Cancer Facts & Figures 2007 [online] (2007).

  2. Lilja, H., Ulmert, D. & Vickers, A. J. Prostate-specific antigen and prostate cancer: prediction, detection and monitoring. Nature Rev. Cancer 8, 268–278 (2008).

    Article  CAS  Google Scholar 

  3. Denmeade, S. R. & Isaacs, J. T. A history of prostate cancer treatment. Nature Rev. Cancer 2, 389–396 (2002).

    Article  CAS  Google Scholar 

  4. Loeb, S. & Catalona, W. J. Prostate-specific antigen in clinical practice. Cancer Lett. 249, 30–39 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005). This manuscript reported the discovery of recurrent gene fusions in a majority of prostate cancers.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Ren, R. Mechanisms of BCR–ABL in the pathogenesis of chronic myelogenous leukaemia. Nature Rev. Cancer 5, 172–183 (2005).

    Article  CAS  Google Scholar 

  8. Goldman, J. M. & Melo, J. V. Chronic myeloid leukemia—advances in biology and new approaches to treatment. N. Engl. J. Med. 349, 1451–1464 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. 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 

  10. Nowell, P. C. & Hungerford, D. A. Chromosome studies in human leukemia. II. Chronic granulocytic leukemia. J. Natl Cancer Inst. 27, 1013–1035 (1961). References 9 & 10 were the first reports of the association between a chromosomal aberration (Philadelphia chromosome) and a malignancy (CML).

    CAS  PubMed  Google Scholar 

  11. Rowley, J. D. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243, 290–293 (1973).

    Article  CAS  PubMed  Google Scholar 

  12. Rowley, J. D. Chromosome translocations: dangerous liaisons revisited. Nature Rev. Cancer 1, 245–250 (2001).

    Article  CAS  Google Scholar 

  13. Druker, B. J. et al. Activity of a specific inhibitor of the BCR–ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N. Engl. J. Med. 344, 1038–1042 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Druker, B. J. et al. Efficacy and safety of a specific inhibitor of the BCR–ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344, 1031–1037 (2001). References 13 and 14 established Gleevec/imatinib as a specific inhibitor of BCR–ABL1 in CML.

    Article  CAS  PubMed  Google Scholar 

  15. Mitelman, F., Mertens, F. & Johansson, B. Prevalence estimates of recurrent balanced cytogenetic aberrations and gene fusions in unselected patients with neoplastic disorders. Genes Chromosomes Cancer 43, 350–366 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Kumar-Sinha, C., Tomlins, S. A. & Chinnaiyan, A. M. Evidence of recurrent gene fusions in common epithelial tumors. Trends Mol. Med. (2006).

  17. Mitelman, F. Recurrent chromosome aberrations in cancer. Mutat. Res. 462, 247–253 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Mitelman, F., Johansson, B., Mandahl, N. & Mertens, F. Clinical significance of cytogenetic findings in solid tumors. Cancer Genet. Cytogenet. 95, 1–8 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Mitelman, F., Johansson, B. & Mertens, F. Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer. Nature Genet. 36, 331–334 (2004). Based on an analysis of prevalence of gene fusions across all cancer types, the authors observed: “Our results support the unorthodox concept that cytogenetic aberrations resulting in deregulated or rearranged genes may be of greater importance as an initial step in epithelial tumorigenesis than generally believed.”

    Article  CAS  PubMed  Google Scholar 

  20. Narod, S. A. & Foulkes, W. D. BRCA1 and BRCA2: 1994 and beyond. Nature Rev. Cancer 4, 665–676 (2004).

    Article  CAS  Google Scholar 

  21. Jeter, J. M., Kohlmann, W. & Gruber, S. B. Genetics of colorectal cancer. Oncology (Williston Park) 20, 269–276; discussion 285–286, 288–289 (2006).

    Google Scholar 

  22. Rowley, P. T. Inherited susceptibility to colorectal cancer. Annu. Rev. Med. 56, 539–554 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Rhodes, D. R. et al. Molecular concepts analysis links tumors, pathways, mechanisms, and drugs. Neoplasia 9, 443–454 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rhodes, D. R. et al. Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia 9, 166–180 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rhodes, D. R. et al. Mining for regulatory programs in the cancer transcriptome. Nature Genet. 37, 579–583 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Rhodes, D. R. et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6, 1–6 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Oikawa, T. & Yamada, T. Molecular biology of the Ets family of transcription factors. Gene 303, 11–34 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Sorensen, P. H. et al. A second Ewing's sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG. Nature Genet. 6, 146–151 (1994).

    Article  CAS  PubMed  Google Scholar 

  30. Adams, J. M. et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318, 533–538 (1985).

    Article  CAS  PubMed  Google Scholar 

  31. Taub, R. et al. Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc. Natl Acad. Sci. USA 79, 7837–7841 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tsujimoto, Y., Finger, L. R., Yunis, J., Nowell, P. C. & Croce, C. M. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 226, 1097–1099 (1984).

    Article  CAS  PubMed  Google Scholar 

  33. Tomlins, S. A. et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 448, 595–599 (2007). This paper reported four novel classes of Ets gene fusions in prostate cancer, besides TMPRSS2 , indicating a complex texture of gene fusions in solid cancers

    Article  CAS  PubMed  Google Scholar 

  34. 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 

  35. 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 

  36. Hermans, K. G. et al. Two unique novel prostate-specific and androgen-regulated fusion partners of ETV4 in prostate cancer. Cancer Res. 68, 3094–3098 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. MacDonald, J. W. & Ghosh, D. COPA—cancer outlier profile analysis. Bioinformatics 22, 2950–2951 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Tibshirani, R. & Hastie, T. Outlier sums for differential gene expression analysis. Biostatistics 8, 2–8 (2007).

    Article  PubMed  Google Scholar 

  39. Annunziata, C. M. et al. Frequent engagement of the classical and alternative NF-κB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 12, 115–130 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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 

  41. Cerveira, N. et al. TMPRSS2ERG gene fusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions. Neoplasia 8, 826–832 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Clark, J. et al. Diversity of TMPRSS2–ERG fusion transcripts in the human prostate. Oncogene 26, 2667–2673 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. 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 

  44. 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 

  45. Mehra, R. et al. Characterization of TMPRSS2ETS gene aberrations in androgen-independent metastatic prostate cancer. Cancer Res. 68, 3584–3590 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hermans, K. G. et al. TMPRSS2:ERG fusion by translocation or interstitial deletion is highly relevant in androgen-dependent prostate cancer, but is bypassed in late-stage androgen receptor-negative prostate cancer. Cancer Res. 66, 10658–10663 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Iljin, K. et al. TMPRSS2 fusions with oncogenic ETS factors in prostate cancer involve unbalanced genomic rearrangements and are associated with HDAC1 and epigenetic reprogramming. Cancer Res. 66, 10242–10246 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. 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 

  49. Rajput, A. B. et al. Frequency of the TMPRSS2:ERG gene fusion is increased in moderate to poorly differentiated prostate cancers. J. Clin. Pathol. 60, 1238–1243 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Soller, M. J. et al. Confirmation of the high frequency of the TMPRSS2/ERG fusion gene in prostate cancer. Genes Chromosomes Cancer 45, 717–719 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Yoshimoto, M. et al. Three-color FISH analysis of TMPRSS2/ERG fusions in prostate cancer indicates that genomic microdeletion of chromosome 21 is associated with rearrangement. Neoplasia 8, 465–469 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wang, J., Cai, Y., Ren, C. & Ittmann, M. Expression of variant TMPRSS2/ERG fusion messenger RNAs is associated with aggressive prostate cancer. Cancer Res. 66, 8347–8351 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. 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 

  54. Melo, J. V. The diversity of BCR–ABL fusion proteins and their relationship to leukemia phenotype. Blood 88, 2375–2384 (1996).

    CAS  PubMed  Google Scholar 

  55. Lynch, H. T., Smyrk, T. & Lynch, J. F. Overview of natural history, pathology, molecular genetics and management of HNPCC (Lynch Syndrome). Int. J. Cancer 69, 38–43 (1996).

    Article  CAS  PubMed  Google Scholar 

  56. Halvarsson, B. et al. Phenotypic heterogeneity in hereditary non-polyposis colorectal cancer: identical germline mutations associated with variable tumour morphology and immunohistochemical expression. J. Clin. Pathol. 60, 781–786 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Lakhani, S. R. et al. Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J. Natl Cancer Inst. 90, 1138–1145 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. Lakhani, S. R. The pathology of familial breast cancer: Morphological aspects. Breast Cancer Res. 1, 31–35 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mosquera, J. M. et al. Morphological features of TMPRSS2ERG gene fusion prostate cancer. J. Pathol. 212, 91–101 (2007).

    Article  PubMed  Google Scholar 

  60. Tu, J. J. et al. Gene fusions between TMPRSS2 and ETS family genes in prostate cancer: frequency and transcript variant analysis by RT-PCR and FISH on paraffin-embedded tissues. Mod. Pathol. 20, 921–928 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. 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 

  62. Nami, 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  Google Scholar 

  63. Nam, R. K. et al. Expression of the TMPRSS2:ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer. Br. J. Cancer 97, 1690–1695 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Attard, G. et al. Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene 27, 253–263 (2007). This paper analysed the prognosis of prostate cancer patients with respect to their TMPRSS2 ERG rearrangement status and concluded that duplication of the fusion is associated with very poor cause-specific survival (25% survival at 8 years) compared with ERG rearrangement-negative cases (90% survival at 8 years).

    Google Scholar 

  65. Petrovics, G. et al. Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome. Oncogene 24, 3847–3852 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Winnes, M., Lissbrant, E., Damber, J. E. & Stenman, G. Molecular genetic analyses of the TMPRSS2ERG and TMPRSS2ETV1 gene fusions in 50 cases of prostate cancer. Oncol. Rep. 17, 1033–1036 (2007).

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  68. 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 

  69. Barry, M., Perner, S., Demichelis, F. & Rubin, M. A. TMPRSS2ERG fusion heterogeneity in multifocal prostate cancer: clinical and biologic implications. Urology 70, 630–633 (2007).

    Article  PubMed  Google Scholar 

  70. Clark, J. et al. Complex patterns of ETS gene alteration arise during cancer development in the human prostate. Oncogene 27, 1993–2003 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Mehra, R. et al. Characterization of TMPRSS2–ETS gene aberrations in androgen independent metastatic prostate cancer. Cancer Res. 68, 3584–3590 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Skoda, R. & Prchal, J. T. Lessons from familial myeloproliferative disorders. Semin. Hematol. 42, 266–273 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Langeberg, W. J., Isaacs, W. B. & Stanford, J. L. Genetic etiology of hereditary prostate cancer. Front. Biosci. 12, 4101–4110 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Setlur, S. R. et al. Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer. J. Natl Cancer Inst. 100, 915–925 (2008).

    Article  CAS  Google Scholar 

  75. Bonkhoff, H., Fixemer, T., Hunsicker, I. & Remberger, K. Estrogen receptor expression in prostate cancer and premalignant prostatic lesions. Am. J. Pathol. 155, 641–647 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Glinsky, G. V., Glinskii, A. B., Stephenson, A. J., Hoffman, R. M. & Gerald, W. L. Gene expression profiling predicts clinical outcome of prostate cancer. J. Clin. Invest. 113, 913–923 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Tomlins, S. A. et al. Integrative molecular concept modeling of prostate cancer progression. Nature Genet. 39, 41–51 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Lapointe, J. et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc. Natl Acad. Sci. USA 101, 811–816 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kim, J. H. et al. Integrative analysis of genomic aberrations associated with prostate cancer progression. Cancer Res. 67, 8229–8239 (2007).

    Article  CAS  PubMed  Google Scholar 

  80. Lapointe, J. et al. Genomic profiling reveals alternative genetic pathways of prostate tumorigenesis. Cancer Res. 67, 8504–8510 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Lin, B. et al. Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Res. 59, 4180–4184 (1999).

    CAS  PubMed  Google Scholar 

  82. Afar, D. E. et al. Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia. Cancer Res. 61, 1686–1692 (2001).

    CAS  PubMed  Google Scholar 

  83. Vaarala, M. H., Porvari, K., Kyllonen, A., Lukkarinen, O. & Vihko, P. The TMPRSS2 gene encoding transmembrane serine protease is overexpressed in a majority of prostate cancer patients: detection of mutated TMPRSS2 form in a case of aggressive disease. Int. J. Cancer 94, 705–710 (2001).

    Article  CAS  PubMed  Google Scholar 

  84. Mertz, K. D. et al. Molecular characterization of TMPRSS2–ERG gene fusion in the NCI-H660 prostate cancer cell line: a new perspective for an old model. Neoplasia 9, 200–206 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Cai, C. et al. ETV1 is a novel androgen receptor-regulated gene that mediates prostate cancer cell invasion. Mol. Endocrinol. 21, 1835–1846 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Ellwood-Yen, K. et al. Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell 4, 223–238 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Tomlins, S. A. et al. Role of the TMPRSS2ERG gene fusion in prostate cancer. Neoplasia 10, 177–188 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Klezovitch, O. et al. A causal role for ERG in neoplastic transformation of prostate epithelium. Proc. Natl Acad. Sci. USA 105, 2105–2110 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Klezovitch, O. et al. A causal role for ERG in neoplastic transformation of prostate epithelium. Proc. Natl Acad. Sci USA 105, 2105–2110 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Shaffer, D. R. & Pandolfi, P. P. Breaking the rules of cancer. Nature Med. 12, 14–15 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Crawford, E. D. PSA testing: what is the use? Lancet 365, 1447–1449

  92. Stamey, T. A. et al. The prostate specific antigen era in the United States is over for prostate cancer: what happened in the last 20 years? J. Urol. 172, 1297–1301 (2004).

    Article  PubMed  Google Scholar 

  93. Frankel, S., Smith, G. D., Donovan, J. & Neal, D. Screening for prostate cancer. Lancet 361, 1122–1128 (2003).

    Article  PubMed  Google Scholar 

  94. 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 

  95. Laxman, B. et al. Noninvasive detection of TMPRSS2:ERG fusion transcripts in the urine of men with prostate cancer. Neoplasia 8, 885–888 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Laxman, B. et al. A first generation multiplex biomarker analysis of urine for the early detection of prostate cancer. Cancer Res. 68, 645–649 (2007).

    Article  Google Scholar 

  97. 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  PubMed  Google Scholar 

  98. Huggins, C. & Hodges, C. V. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1, 5 (1941).

    Google Scholar 

  99. Huggins, C., Stevens, R. E. & Hodges, C. V. Studies on prostatic cancer: 2. The effects of castration on advanced carcinoma of the prostate gland. Arch. Surg. 43 209–222 (1941). References 98 and 99 mark the pioneering work of C. Huggins and C. V. Hodges that introduced androgen ablation therapy as a treatment modality for prostate cancer.

    Article  CAS  Google Scholar 

  100. Schally, A. V., Kastin, A. J. & Arimura, A. Hypothalamic FSH and LH-regulating hormone. Structure, physiology and clinical studies. Fertil. Steril. 22, 703–721 (1971).

    Article  CAS  PubMed  Google Scholar 

  101. Denmeade, S. R. & Isaacs, J. T. in Cancer Medicine 5th edn (eds Bast, R. C. et al.) 765–776 (B. C. Decker, Hamilton, Ontario, 2000).

    Google Scholar 

  102. Steinberg, G. D. & Isaacs, J. T. in Cancer Chemotherapy (eds Hickman, J. A. & Hitton, T. R.) 322–341 (Blackwell Scientific Publications, Oxford, 1993).

    Google Scholar 

  103. Varenhorst, E., Wallentin, L. & Carlstrom, K. The effects of orchidectomy, estrogens, and cyproterone acetate on plasma testosterone, LH, and FSH concentrations in patients with carcinoma of the prostate. Scand. J. Urol. Nephrol. 16, 31–36 (1982).

    Article  CAS  PubMed  Google Scholar 

  104. Liao, S., Howell, D. K. & Chang, T. M. Action of a nonsteroidal antiandrogen, flutamide, on the receptor binding and nuclear retention of 5 α-dihydrotestosterone in rat ventral prostate. Endocrinology 94, 1205–1209 (1974).

    Article  CAS  PubMed  Google Scholar 

  105. Maximum androgen blockage in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. Lancet 346, 265–269 (1995).

  106. Laufer, M., Denmeade, S. R., Sinibaldi, V., Carducci, M. & Eisenberger, M. A. Complete androgen blockade for prostate cancer: What went wrong? J. Urol. 164, 3–9 (2000).

    Article  CAS  PubMed  Google Scholar 

  107. Soda, M. et al. Identification of the transforming EML4ALK fusion gene in non-small-cell lung cancer. Nature 448, 561–566 (2007). The first report of a recurrent gene fusion in lung cancer.

    Article  CAS  PubMed  Google Scholar 

  108. Rikova, K. et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131, 14 (2007).

    Article  CAS  Google Scholar 

  109. Korbel, J. O. et al. Paired-end mapping reveals extensive structural variation in the human genome. Science 318, 420–426 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ruan, Y. et al. Fusion transcripts and transcribed retrotransposed loci discovered through comprehensive transcriptome analysis using Paired-End diTags (PETs). Genome Res. 17, 828–838 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Rabbitts, T. H. Chromosomal translocations in human cancer. Nature 372, 143–149 (1994).

    Article  CAS  PubMed  Google Scholar 

  112. Gleissner, B. et al. Leading prognostic relevance of the BCR–ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis. Blood 99, 1536–1543 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Ribeiro, R. C. et al. Clinical and biologic hallmarks of the Philadelphia chromosome in childhood acute lymphoblastic leukemia. Blood 70, 948–953 (1987).

    CAS  PubMed  Google Scholar 

  114. Nowell, P. C. & Hungerford, D. A. A minute chromosome in human chronic granulocytic leukemia. Science 132, 1497–1501 (1960).

    Google Scholar 

  115. Hughes, T. et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 108, 28–37 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lugo, T. G., Pendergast, A. M., Muller, A. J. & Witte, O. N. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 247, 1079–1082 (1990).

    Article  CAS  PubMed  Google Scholar 

  117. Daley, G. Q., Van Etten, R. A. & Baltimore, D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247, 824–830 (1990).

    Article  CAS  PubMed  Google Scholar 

  118. Elefanty, A. G., Hariharan, I. K. & Cory, S. bcr-abl, the hallmark of chronic myeloid leukaemia in man, induces multiple haemopoietic neoplasms in mice. EMBO J. 9, 1069–1078 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Kelliher, M. A., McLaughlin, J., Witte, O. N. & Rosenberg, N. Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL. Proc. Natl Acad. Sci. USA 87, 6649–6653 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Koschmieder, S. et al. Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR–ABL leukemogenesis. Blood 105, 324–334 (2005).

    Article  CAS  PubMed  Google Scholar 

  121. Druker, B. J. et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N. Engl. J. Med. 355, 2408–2417 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. Hughes, T. P. et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N. Engl. J. Med. 349, 1423–1432 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. O'Brien, S. G. et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 348, 994–1004 (2003).

    Article  CAS  PubMed  Google Scholar 

  124. Jhavar, S. et al. Detection of TMPRSS2ERG translocations in human prostate cancer by expression profiling using GeneChip Human Exon 1.0 ST arrays. J. Mol. Diagn. 10, 50–57 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We apologize to all the authors whose work could not be included in this manuscript owing to space constraints. We thank J. Granger for her scientific editorial assistance. We thank R. Mehra, N. Palanisamy, and S. M. Dhanasekaran for useful discussions. We thank R. Kunkel for help with the artwork for figures. This work was supported in part by Department of Defense, the National Institutes of Health, the Early Detection Research Network, and the Prostate Cancer Foundation grants to A.M.C. A.M.C. is supported by a Clinical Translational Research Award from the Burroughs Wellcome Foundation. S.A.T. is a Fellow of the Medical Scientist Training Program and is supported by the GPC Biotech Young Investigator Award from the Prostate Cancer Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Arul M. Chinnaiyan.

Ethics declarations

Competing interests

The University of Michigan has filed for a patent on the recurrent gene fusions in prostate cancer and S.A.T. and A.M.C. are named as co-inventors. The technology has been licensed to Gen-Probe Inc. to developed a molecular diagnostic. A.M.C. is a consultant to Gen-Probe.

Related links

Related links

DATABASES

National Cancer Institute

breast cancer

Ewing sarcoma

lung cancer

lymphoma

multiple myeloma

prostate cancer

National Cancer Institute Drug Dictionary

bicalutamide

cyproterone acetate

flutamide

gefitinib

imatinib

nilutamide

FURTHER INFORMATION

A. M. Chinnaiyan's Laboratory homepage

Michigan Center for Translational Pathology

Atlas of Genetics and Cytogenetics

COPA package in R

COPA package integrated into SAM

Mitelman Database

Oncomine

Glossary

Androgen ablation

A core prostate cancer treatment modality that involves severing androgen signalling in prostate cancer either by physical means (castration) or biochemically (by injecting oestrogens, anti-androgens, or androgen receptor agonists or antagonists). Charles Huggins was awarded the Nobel Prize in Physiology or Medicine in 1966 for this development in 1941.

Ets

The E26 transformation-specific family of genes encode nuclear transcription factors, characterized by DNA-binding Ets domains and various protein interaction domains. Ets family proteins are involved in cell growth, signal transduction, cell cycle regulation, apoptosis, haematopoietic, neuronal and myogenic differentiation, and in several human malignancies, such as Ewing tumours, leukaemias and prostate cancer.

Gene fusion

A physical linking of two genes (typically accompanied by deletion of portions of the two partner genes) such that they come to share a common regulatory element and/or open reading frames, the latter encoding chimeric proteins, for example BCR–ABL1 or TMPRSS2–ERG.

Prostatic intraepithelial neoplasia

(PIN). This defines foci of rapidly dividing prostate epithelial cells, believed to be the precursor of prostate cancer. PINs are typically classified as high-grade, medium-grade and low-grade, depending on their level of differentiation. Approximately one-third of men with high-grade PIN develop prostate cancer.

Interstitial deletion

Loss of material from within a chromosome, not involving the ends (telomeres).

Molecular Concepts Map

(MCM). Gene expression signatures of sets of biologically connected genes, such as 'lipid biosynthesis genes' or 'androgen-activated genes'. have been defined as 'molecular concepts'. Over 40,000 such concepts have been compiled in Oncomine. The MCM involves interrogating a set of user-defined genes (such as an expression signature or genes identified in a functional screen) against all concepts in the MCM to identify molecular networks enriched in the query set.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kumar-Sinha, C., Tomlins, S. & Chinnaiyan, A. Recurrent gene fusions in prostate cancer. Nat Rev Cancer 8, 497–511 (2008). https://doi.org/10.1038/nrc2402

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2402

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing