Skip to main content

Advertisement

SpringerLink
Log in

FGFR3 mutations, but not FGFR3 expression and FGFR3 copy-number variations, are associated with favourable non-muscle invasive bladder cancer

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

The fibroblast growth factor receptor 3 (FGFR3) is a tyrosine kinase receptor frequently activated by point mutations in bladder cancer (BC). These mutations are associated with genetically stable, Ta and low-grade BC, representing the favourable BC pathway. Conversely, FGFR3 over-expression was recently found in 40 % of muscle invasive BC. We examined FGFR3 mutation status and protein expression in patients originally diagnosed as T1. We also investigated copy-number variations in FGFR3 as a possible alternative mechanism to activate FGFR3. We included 84 patients with T1 BC as their initial diagnosis. A uropathologist reviewed the slides for grade and (sub)stage. The FGFR3 mutation status was examined by PCR-SNaPshot and FGFR3 protein expression by standard immuno-histochemistry (FGFR3-B9). Copy-number status was determined in 69/84 cases with nine probes covering nine exons of the FGFR3 gene (MLPA). Of 27 BC with FGFR3 mutations, 26 (96 %) showed FGFR3 over-expression. Of the 57 wild-type BC, 27 (47 %) BC showed over-expression. Pathological parameters significantly differed (p < 0.01) between mutant and wild-type tumours with the FGFR3 mutation pointing to more favourable BC. However, if the BC exhibited wild-type FGFR3, FGFR3 protein status had no influence on grade and (sub)stage. We found six tumours with more than or equal to three copies of FGFR3. Only 1 of 22 wild-type tumours with over-expression of FGFR3 had more than or equal to three gene copies. In initially diagnosed T1 BC, only the FGFR3 mutation was significantly associated with favourable BC disease characteristics. In addition to almost all FGFR3 mutant BC, 47 % of wild-type BC displayed FGFR3 over-expression, suggesting an alternative mechanism to activate FGFR3. Increased FGFR3 copy number was a rare event and did not account for this mechanism. Nevertheless, FGFR3 wild-type tumours with over-expression of the protein may still represent a subset that might potentially benefit from FGFR3-targeted therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Siegel R, Naishadham D, Jemal A (2013) Cancer statistics. CA Cancer J Clin 63:11–30. doi:10.3322/caac.21166

    Article  PubMed  Google Scholar 

  2. Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, Newling DW, Kurth K (2006) Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 49:466–475

    Article  PubMed  Google Scholar 

  3. van Rhijn BW, Vis AN, van der Kwast TH, Kirkels WJ, Radvanyi F, Ooms EC, Chopin DK, Boevé ER, Jöbsis AC, Zwarthoff EC (2003) Molecular grading of urothelial cell carcinoma with fibroblast growth factor receptor 3 and MIB-1 is superior to pathologic grade for the prediction of clinical outcome. J Clin Oncol 21:1912–1921

    Article  PubMed  Google Scholar 

  4. di Martino E, Tomlinson DC, Knowles MA (2012) A decade of FGF receptor research in bladder cancer: past, present, and future challenges. Adv Urol 2012:429213. doi:10.1155/2012/429213

    Article  PubMed  PubMed Central  Google Scholar 

  5. van Rhijn BW, van der Kwast TH, Vis AN, Kirkels WJ, Boevé ER, Jöbsis AC, Zwarthoff EC (2004) FGFR3 and P53 characterize alternative genetic pathways in the pathogenesis of urothelial cell carcinoma. Cancer Res 64:1911–1914

    Article  PubMed  Google Scholar 

  6. Hernández S, López-Knowles E, Lloreta J, Kogevinas M, Amorós A, Tardón A, Carrato A, Serra C, Malats N, Real FX (2006) Prospective study of FGFR3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas. J Clin Oncol 24:3664–3671

    Article  PubMed  Google Scholar 

  7. Mhawech-Fauceglia P, Fischer G, Alvarez V Jr, Ahmed A, Herrmann FR (2007) Predicting outcome in minimally invasive (T1a and T1b) urothelial bladder carcinoma using a panel of biomarkers: a high throughput tissue microarray analysis. BJU Int 100:1182–1187

    PubMed  Google Scholar 

  8. Barbisan F, Santinelli A, Mazzucchelli R, Lopez-Beltran A, Cheng L, Scarpelli M, van der Kwast T, Montironi R (2008) Strong immunohistochemical expression of fibroblast growth factor receptor 3, superficial staining pattern of cytokeratin 20, and low proliferative activity define those papillary urothelial neoplasms of low malignant potential that do not recur. Cancer 112:636–644

    Article  PubMed  Google Scholar 

  9. Matsumoto M, Ohtsuki Y, Ochii K, Seike Y, Iseda N, Sasaki T, Okada Y, Kurabayashi A, Furihata M (2004) Fibroblast growth factor receptor 3 protein expression in urothelial carcinoma of the urinary bladder, exhibiting no association with low-grade and/or non-invasive lesions. Oncol Rep 12:967–971

    CAS  PubMed  Google Scholar 

  10. Tomlinson DC, Baldo O, Harnden P, Knowles MA (2007) FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J Pathol 213:91–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bodoor K, Ghabkari A, Jaradat Z, Alkhateeb A, Jaradat S, Al-Ghazo MA, Matalka I, Musleh H, Haddad Y (2010) FGFR3 mutational status and protein expression in patients with bladder cancer in a Jordanian population. Cancer Epidemiol 34:724–732

    Article  CAS  PubMed  Google Scholar 

  12. van Oers JM, Lurkin I, van Exsel AJ, Nijsen Y, van Rhijn BW, van der Aa MN, Zwarthoff EC (2005) A simple and fast method for the simultaneous detection of nine fibroblast growth factor receptor 3 mutations in bladder cancer and voided urine. Clin Cancer Res 11:7743–7748

    Article  PubMed  Google Scholar 

  13. Otto W, Denzinger S, Bertz S, Gaumann A, Wild PJ, Hartmann A, Stoehr R (2009) No mutations of FGFR3 in normal urothelium in the vicinity of urothelial carcinoma of the bladder harbouring activating FGFR3 mutations in patients with bladder cancer. Int J Cancer 125:2205–2208

    Article  CAS  PubMed  Google Scholar 

  14. Billerey C, Chopin D, Aubriot-Lorton MH, Ricol D, Diez G, de Medina S, Van Rhijn B, Bralet MP, Lefrere-Belda MA, Lahaye JB, Abbou CC, Bonaventure J, Zafrani ES, van der Kwast T, Thiery JP, Radvanyi F (2001) Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. Am J Pathol 158:1955–1959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Neuzillet Y, Paoletti X, Ouerhani S, Mongiat-Artus P, Soliman H, de The H, Sibony M, Denoux Y, Molinie V, Herault A, Lepage ML, Maille P, Renou A, Vordos D, Abbou CC, Bakkar A, Asselain B, Kourda N, El Gaaied A, Leroy K, Laplanche A, Benhamou S, Lebret T, Allory Y, Radvanyi F (2012) A meta-analysis of the relationship between FGFR3 and TP53 mutations in bladder cancer. PLoS One 7:e48993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gómez-Román JJ, Saenz P, Molina M, Cuevas González J, Escuredo K, Santa Cruz S, Junquera C, Simón L, Martínez A, Gutiérrez Baños JL, López-Brea M, Esparza C, Val-Bernal JF (2005) Fibroblast growth factor receptor 3 is overexpressed in urinary tract carcinomas and modulates the neoplastic cell growth. Clin Cancer Res 11:459–465

    PubMed  Google Scholar 

  17. Nord H, Segersten U, Sandgren J, Wester K, Busch C, Menzel U, Komorowski J, Dumanski JP, Malmström PU, Díaz de Ståhl T (2010) Focal amplifications are associated with high grade and recurrences in stage Ta bladder carcinoma. Int J Cancer 126:1390–1402

    CAS  PubMed  Google Scholar 

  18. Knowles MA (2006) Molecular subtypes of bladder cancer: Jekyll and Hyde or chalk and cheese? Carcinogenesis 27:361–373

    Article  CAS  PubMed  Google Scholar 

  19. Wu XR (2005) Urothelial tumorigenesis: a tale of divergent pathways. Nat Rev Cancer 5:713–725

    Article  CAS  PubMed  Google Scholar 

  20. Vékony H, Ylstra B, Wilting SM, Meijer GA, van de Wiel MA, Leemans CR, van der Waal I, Bloemena E (2007) DNA copy-number gains at loci of growth factors and their receptors in salivary gland adenoid cystic carcinoma. Clin Cancer Res 13:3133–3139

    Article  PubMed  Google Scholar 

  21. Chesi M, Nardini E, Brents LA, Schröck E, Ried T, Kuehl WM, Bergsagel PL (1997) Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nat Genet 16:260–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Williams SV, Hurst CD, Knowles MA (2013) Oncogenic FGFR3 gene fusions in bladder cancer. Hum Mol Genet 22:795–803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lindgren D, Liedberg F, Andersson A, Chebil G, Gudjonsson S, Borg A, Månsson W, Fioretos T, Höglund M (2006) Molecular characterization of early-stage bladder carcinomas by expression profiles, FGFR3 mutation status, and loss of 9q. Oncogene 25:2685–2696

    Article  CAS  PubMed  Google Scholar 

  24. Karkoulis PK, Stravopodis DJ, Konstantakou EG, Voutsinas GE (2013) Targeted inhibition of heat shock protein 90 disrupts multiple oncogenic signaling pathways, thus inducing cell cycle arrest and programmed cell death in human urinary bladder cancer cell lines. Cancer Cell Int 13:11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Liu GH, Zhong Q, Ye YL, Wang HB, Hu LJ, Qin ZK, Zeng MS, Zeng BH (2013) Expression of beclin 1 in bladder cancer and its clinical significance. Int J Biol Markers 28:56–62

    Article  PubMed  Google Scholar 

  26. Dolloff NG, Talamo G (2013) Targeted therapy of multiple myeloma. Adv Exp Med Biol 779:197–221

    Article  PubMed  Google Scholar 

  27. Bernard-Pierrot I, Brams A, Dunois-Lardé C, Caillault A, Diez de Medina SG, Cappellen D, Graff G, Thiery JP, Chopin D, Ricol D, Radvanyi F (2006) Oncogenic properties of the mutated forms of fibroblast growth factor receptor 3b. Carcinogenesis 27:740–747

    Article  CAS  PubMed  Google Scholar 

  28. Tomlinson DC, Hurst CD, Knowles MA (2007) Knockdown by shRNA identifies S249C mutant FGFR3 as a potential therapeutic target in bladder cancer. Oncogene 26:5889–5899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Simone Russell, Rati Vajpeyi, Sally Hanna, Roni Sambas and Cynthia Kuk for help and advice. The Regional Ethics Board of the University Health Network, Toronto (02-0515-C and 08-0263-T), gave approval. Financial support was given by the University of Toronto and by a grant from the Dutch Cancer Society – KWF Kankerbestrijding.

Conflict of interest

None

Author information

Authors and Affiliations

  1. Department of Surgical Oncology (Urology), The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Yann Neuzillet & Bas W. G. van Rhijn

  2. Department of Urology, Foch Hospital, University of Versailles – Saint-Quentin-en-Yveline (UVSQ), Suresnes, France

    Yann Neuzillet

  3. Department of Surgical Oncology (Urology), Princess Margaret Hospital, University Health Network, Toronto, ON, Canada

    Bas W. G. van Rhijn, Peter J. Bostrom, Neil E. Fleshner, Alexandre R. Zlotta & Michael A. S. Jewett

  4. Department of Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada

    Bas W. G. van Rhijn, Bharati Bapat & Liyang Liu

  5. Department of Laboratory Medicine, Solutions by Sequence, Toronto Western Hospital, University Health Network, Toronto, ON, Canada

    Nadia L. Prigoda & Brenda L. Gallie

  6. Department of Urology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada

    Alexandre R. Zlotta

  7. Department of Pathology, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada

    Theo H. van der Kwast

Authors
  1. Yann Neuzillet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bas W. G. van Rhijn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nadia L. Prigoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bharati Bapat
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Liyang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peter J. Bostrom
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Neil E. Fleshner
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Brenda L. Gallie
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Alexandre R. Zlotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michael A. S. Jewett
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Theo H. van der Kwast
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bas W. G. van Rhijn.

Additional information

Yann Neuzillet, Bas W. G. van Rhijn and Nadia L. Prigoda contributed equally to this article

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Neuzillet, Y., van Rhijn, B.W.G., Prigoda, N.L. et al. FGFR3 mutations, but not FGFR3 expression and FGFR3 copy-number variations, are associated with favourable non-muscle invasive bladder cancer. Virchows Arch 465, 207–213 (2014). https://doi.org/10.1007/s00428-014-1596-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-014-1596-4

Keywords

Search

Navigation