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.

  • Original Article
  • Published:

Complex patterns of ETS gene alteration arise during cancer development in the human prostate

Oncogene volume 27, pages 1993–2003 (2008)Cite this article

Abstract

An ERG gene ‘break-apart’ fluorescence in situ hybridization (FISH) assay has been used to screen whole-mount prostatectomy specimens for rearrangements at the ERG locus. In cancers containing ERG alterations the observed pattern of changes was often complex. Different categories of ERG gene alteration were found either together in a single cancerous region or within separate foci of cancer in the same prostate slice. In some cases the juxtaposition of particular patterns of ERG alterations suggested possible mechanisms of tumour progression. Prostates harbouring ERG alterations commonly also contained cancer that lacked rearrangements of the ERG gene. A single trans-urethral resection of the prostate specimen examined harboured both ERG and ETV1 gene rearrangements demonstrating that the observed complexity may, at least in part, be explained by multiple ETS gene alterations arising independently in a single prostate. In a search for possible precursor lesions clonal ERG rearrangements were found both in high grade prostatic intraepithelial neoplasia (PIN) and in atypical in situ epithelial lesions consistent with the diagnosis of low grade PIN. Our observations support the view that ERG gene alterations represent an initiating event that promotes clonal expansion initially to form regions of epithelial atypia. The complex patterns of ERG alteration found in prostatectomy specimens have important implications for the design of experiments investigating the clinical significance and mechanism of development of individual prostate cancers.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 4
Figure 2
Figure 3
Figure 5
Figure 6

Similar content being viewed by others

References

  • Aihara M, Wheeler TM, Ohori M, Scardino PT . (1994). Heterogeneity of prostate cancer in radical prostatectomy specimens. Urology 43: 60–66.

    Article  CAS  PubMed  Google Scholar 

  • Arora R, Koch MO, Eble JN, Ulbright TM, Li L, Cheng L . (2004). Heterogeneity of Gleason grade in multifocal adenocarcinoma of the prostate. Cancer 100: 2362–2366.

    Article  PubMed  Google Scholar 

  • Attard G, Clark J, Ambroisine L, Fisher G, Kovacs G, Flohr P et al. (2007). Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene; e-pub ahead of print: 16 July 2007.

  • Bostwick DG, Shan A, Qian J, Darson M, Maihle NJ, Jenkins RB et al. (1998). Independent origin of multiple foci of prostatic intraepithelial neoplasia: comparison with matched foci of prostate carcinoma. Cancer 83: 1995–2002.

    Article  CAS  PubMed  Google Scholar 

  • Brawer MK, Bigler SA, Sohlberg OE, Nagle RB, Lange PH . (1991). Significance of prostatic intraepithelial neoplasia on prostate needle biopsy. Urology 38: 103–107.

    Article  CAS  PubMed  Google Scholar 

  • Cerveira N, Ribeiro FR, Peixoto A, Costa V, Henrique R, Jeronimo C et al. (2006). TMPRSS2–ERG gene fusion causing erg overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions. Neoplasia 8: 826–832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen ME, Johnston DA, Tang K, Babaian RJ, Troncoso P . (2000). Detailed mapping of prostate carcinoma foci: biopsy strategy implications. Cancer 89: 1800–1809.

    Article  CAS  PubMed  Google Scholar 

  • Cheng L, Song SY, Pretlow TG, Abdul-Karim FW, Kung HJ, Dawson DV et al. (1998). Evidence of independent origin of multiple tumors from patients with prostate cancer. J Natl Cancer Inst 90: 233–237.

    Article  CAS  PubMed  Google Scholar 

  • Chun FK, Briganti A, Jeldres C, Erbersdobler A, Schlomm T, Steuber T et al. (2007). Zonal origin of localized prostate cancer does not affect the rate of biochemical recurrence after radical prostatectomy. Eur Urol 51: 949–955.

    Article  PubMed  Google Scholar 

  • Clark J, Merson S, Jhavar S, Flohr P, Edwards S, Foster CS et al. (2006). Diversity of TMPRSS2–ERG fusion transcripts in the human prostate. Oncogene 26: 2667–2673.

    Article  PubMed  Google Scholar 

  • Cuzick J, Fisher C, Kattan MW, Berney D, Oliver T, Foster CS et al. (2006). Long-term outcome among men with conservatively treated localised prostate cancer. Br J Cancer 95: 1186–1194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Demichelis F, Fall K, Perner S, Andren O, Schmidt F, Setlur SR et al. (2007). TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene 26: 5692.

    Article  CAS  Google Scholar 

  • Djavan B, Susani M, Bursa B, Basharkhah A, Simak R, Marberger M . (1999). Predictability and significance of multifocal prostate cancer in the radical prostatectomy specimen. Tech Urol 5: 139–142.

    Article  CAS  PubMed  Google Scholar 

  • Egevad L, Allsbrook WC, Epstein JI . (2006). Current practice of diagnosis and reporting of prostatic intraepithelial neoplasia and glandular atypia among genitourinary pathologists. Mod Pathol 19: 180–185.

    Article  PubMed  Google Scholar 

  • Epstein JI, Grignon DJ, Humphrey PA, McNeal JE, Sesterhenn IA, Troncoso P et al. (1995). Interobserver reproducibility in the diagnosis of prostatic intraepithelial neoplasia. Am J Surg Pathol 19: 873–886.

    Article  CAS  PubMed  Google Scholar 

  • Foster CS . (2000). Pathology of benign prostatic hyperplasia. Prostate Suppl 9: 4–14.

    Article  CAS  PubMed  Google Scholar 

  • Foster CS, Bostwick DG, Bonkhoff H, Damber JE, van der KT, Montironi R et al. (2000). Cellular and molecular pathology of prostate cancer precursors. Scand J Urol Nephrol Suppl, 19–43.

    Article  Google Scholar 

  • Foster CS, Falconer A, Dodson AR, Norman AR, Dennis N, Fletcher A et al. (2004). Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome. Oncogene 23: 5871–5979.

    Article  CAS  PubMed  Google Scholar 

  • Greene DR, Fitzpatrick JM, Scardino PT . (1995). Anatomy of the prostate and distribution of early prostate cancer. Semin Surg Oncol 11: 9–22.

    Article  CAS  PubMed  Google Scholar 

  • Grignon DJ, Sakr WA . (1994). Zonal origin of prostatic adenocarcinoma: are there biologic differences between transition zone and peripheral zone adenocarcinomas of the prostate gland? J Cell Biochem Suppl 19: 267–269.

    CAS  PubMed  Google Scholar 

  • Hermans KG, van Marion R, van Dekken H, Jenster G, van Weerden WM, Trapman J . (2006). 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.

    Article  CAS  PubMed  Google Scholar 

  • Iljin K, Wolf M, Edgren H, Gupta S, Kilpinen S, Skotheim RI et al. (2006). 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.

    Article  CAS  PubMed  Google Scholar 

  • Jenkins RB, Qian J, Lieber MM, Bostwick DG . (1997). Detection of C-Myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization. Cancer Res 57: 524–531.

    CAS  PubMed  Google Scholar 

  • Jhavar SG, Fisher C, Jackson A, Reinsberg SA, Dennis N, Falconer A et al. (2005). Processing of radical prostatectomy specimens for correlation of data from histopathological, molecular biological, and radiological studies: a new whole organ technique. J Clin Pathol 58: 504–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Konishi N, Hiasa Y, Matsuda H, Tao M, Tsuzuki T, Hayashi I et al. (1995). Intratumor cellular heterogeneity and alterations in Ras oncogene and P53 tumor suppressor gene in human prostate carcinoma. Am J Pathol 147: 1112–1122.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lapointe J, Li C, Higgins JP, van de RM, Bair E, Montgomery K et al. (2004). Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc Natl Acad Sci USA 101: 811–816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McNeal JE . (1988). Significance of duct-acinar dysplasia in prostatic carcinogenesis. Prostate 13: 91–102.

    Article  CAS  PubMed  Google Scholar 

  • McNeal JE, Yemoto CE . (1996). Spread of adenocarcinoma within prostatic ducts and acini. Morphologic and clinical correlations. Am J Surg Pathol 20: 802–814.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Mirchandani D, Zheng J, Miller GJ, Ghosh AK, Shibata DK, Cote RJ et al. (1995). Heterogeneity in intratumor distribution of P53 mutations in human prostate cancer. Am J Pathol 147: 92–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nam RK, Sugar L, Wang Z, Yang W, Kitching R, Klotz LH et al. (2007). Expression of TMPRSS2 ERG gene fusion in prostate cancer cells is an important prognostic factor for cancer progression. Cancer Biol Ther 6: 40–45.

    Article  CAS  PubMed  Google Scholar 

  • Perner S, Demichelis F, Beroukhim R, Schmidt FH, Mosquera J-M, Setlur S et al. (2006). TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res 66: 8337–8341.

    Article  CAS  PubMed  Google Scholar 

  • Perner S, Mosquera JM, Demichelis F, Hofer MD, Paris PL, Simko J et al. (2007). TMPRSS2–ERG fusion prostate cancer: an early molecular event associated with invasion. Am J Surg Pathol. 31: 882–888.

    Article  PubMed  Google Scholar 

  • Qian J, Bostwick DG, Takahashi S, Borell TJ, Herath JF, Lieber MM et al. (1995). Chromosomal anomalies in prostatic intraepithelial neoplasia and carcinoma detected by fluorescence in situ hybridization. Cancer Res 55: 5408–5414.

    CAS  PubMed  Google Scholar 

  • Radtke F, Clevers H . (2005). Self-renewal and cancer of the gut: two sides of a coin. Science 307: 1904–1909.

    Article  CAS  PubMed  Google Scholar 

  • Sakai I, Harada K, Hara I, Eto H, Miyake H . (2005). A comparison of the biological features between prostate cancers arising in the transition and peripheral zones. BJU Int 96: 528–532.

    Article  PubMed  Google Scholar 

  • Singh D, Febbo PG, Ross K, Jackson DG, Manola J, Ladd C et al. (2002). Gene expression correlates of clinical prostate cancer behavior. Cancer Cell 1: 203–209.

    Article  CAS  PubMed  Google Scholar 

  • Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H et al. (2001). Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98: 10869–10874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A et al. (2003). Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100: 8418–8423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Srigley JR, Amin MB, Bostwick DG, Grignon DJ, Hammond ME . (2000). Updated protocol for the examination of specimens from patients with carcinomas of the prostate gland: a basis for checklists. Cancer Committee. Arch Pathol Lab Med 124: 1034–1039.

    CAS  PubMed  Google Scholar 

  • Stephenson AJ, Smith A, Kattan MW, Satagopan J, Reuter VE, Scardino PT et al. (2005). Integration of gene expression profiling and clinical variables to predict prostate carcinoma recurrence after radical prostatectomy. Cancer 104: 290–298.

    Article  CAS  PubMed  Google Scholar 

  • Tomlins SA, Mehra R, Rhodes DR, Smith LR, Roulston D, Helgeson BE et al. (2006). TMPRSS2: ETV4 gene fusions define a third molecular subtype of prostate cancer. Cancer Res 66: 3396–3400.

    Article  CAS  PubMed  Google Scholar 

  • Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW et al. (2005). Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310: 644–648.

    Article  CAS  PubMed  Google Scholar 

  • Villers A, McNeal JE, Freiha FS, Stamey TA . (1992). Multiple cancers in the prostate. Morphologic features of clinically recognized versus incidental tumors. Cancer 70: 2313–2318.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Yoshimoto M, Joshua AM, Chilton-Macneill S, Bayani J, Selvarajah S, Evans AJ et al. (2006). 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu YP, Landsittel D, Jing L, Nelson J, Ren B, Liu L et al. (2004). Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J Clin Oncol 22: 2790–2799.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was funded by Cancer Research UK, the National Cancer Research Institute, the Grand Charity of Freemasons and the Rosetrees Trust. We thank Christine Bell for help with typing the manuscript. DMB is supported by The Orchid Appeal.

Author information

Authors and Affiliations

  1. Institute of Cancer Research, Male Urological Cancer Research Centre, Sutton, Surrey, UK

    J Clark, G Attard, S Jhavar, P Flohr, A Reid, J De-Bono, R Eeles, M D Parker & C S Cooper

  2. The Royal Marsden NHS Trust Foundation Hospital, Sutton, Surrey, UK

    G Attard, A Reid, J De-Bono & R Eeles

  3. Department of Urology, Memorial Sloan-Kettering Cancer Centre, New York, NY, USA

    P Scardino

  4. Wolfson Institute of Preventive Medicine, University of London, London, UK

    J Cuzick & G Fisher

  5. Department of Pathology, The University of Liverpool, Royal Liverpool University Hospital, Liverpool, UK

    C S Foster

  6. The Orchid Tissue Laboratory, St Bartholomew's Hospital, London, UK

    D Berney

  7. Laboratory of Molecular Oncology, Medical Faculty, Ruprecht-Karls-University, Heidelberg, Germany

    G Kovacs

Authors
  1. J Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G Attard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Jhavar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P Flohr
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Reid
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J De-Bono
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R Eeles
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P Scardino
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J Cuzick
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. G Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M D Parker
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. C S Foster
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. D Berney
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. G Kovacs
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. C S Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Clark.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clark, J., Attard, G., Jhavar, S. et al. Complex patterns of ETS gene alteration arise during cancer development in the human prostate. Oncogene 27, 1993–2003 (2008). https://doi.org/10.1038/sj.onc.1210843

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210843

Keywords

This article is cited by

Search

Advanced search

Quick links