Skip to main content

Advertisement

Log in

Amplification of FGFR1 gene and expression of FGFR1 protein is found in different histological types of lung carcinoma

Virchows Archiv Aims and scope Submit manuscript

Abstract

Although lung cancer continues to be the leading cause of cancer-related death, accurate diagnosis followed by personalized treatment is expected to raise the 5-year survival rate. Targeted therapies are now in routine clinical use, in particular for lung adenocarcinoma (ADC). Fibroblast growth factor receptor 1 (FGFR1) has recently emerged as a molecular target, especially in squamous cell/epidermoid carcinoma (SQC) of the lung. This paper evaluates FGFR1 expression and gene copy number in adenocarcinomas, squamous cell carcinomas, pleomorphic carcinomas (PLEOMC) and adenosquamous carcinomas (ADSQC) of the lung and also explores the epithelial-mesenchymal transition (EMT) pathway. We studied 76 lung carcinomas: 34 ADC, 24 SQC, 10 PLEOMC and 8 ADSQC. FGFR1 expression was evaluated by immunohistochemistry and gene amplification by fluorescence in situ hybridization (FISH). Higher FGFR1 protein expression was observed in all tumour types compared to non-tumour tissue. FGFR1 expression was higher in ADC and PLEOMC than in SQC. We found a tendency to higher expression in ADC than in SQC and significantly higher expression in PLEOMC than in other histological subtypes. FISH-based amplification of FGFR1 was identified in 15 (20 %) lung carcinomas: 5 (15 %) ADC, 5 (21 %) SQC, 3 (30 %) PLEOMC and 2 (25 %) ADSQC. Amplification was more frequent in SQC without significant differences. FGFR1 protein is expressed in the majority of lung carcinomas, though it is higher in ADC and PLEOMC (the latter may reflect the importance of FGFR1 control of the EMT pathway). FGFR1 amplification was identified in all types of lung carcinoma. Although FGFR1 is most frequently amplified in SQC, other histological types merit assessment of FGFR1 amplification, in order to select patients that might benefit from targeted therapy.

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

Access this article

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

Similar content being viewed by others

References

  1. Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistics, 2014. CA Cancer J Clin 64:9–29

    Article  PubMed  Google Scholar 

  2. Schultheis AM, Bos M, Schmitz K, Wilsberg L, Binot E, et al. (2013) Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential therapeutic target in small-cell lung cancer. Mod Pathol

  3. Shaw AT, Yeap BY, Solomon BJ, Riely GJ, Gainor J, et al. (2011) Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 12:1004–1012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, et al. (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380–2388

    Article  CAS  PubMed  Google Scholar 

  5. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, et al. (2010) Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 11:121–128

    Article  CAS  PubMed  Google Scholar 

  6. Weiss J, Sos ML, Seidel D, Peifer M, Zander T, et al. (2010) Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med 2:62ra93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10:116–129

    Article  CAS  PubMed  Google Scholar 

  8. Dailey L, Ambrosetti D, Mansukhani A, Basilico C (2005) Mechanisms underlying differential responses to FGF signaling. Cytokine Growth Factor Rev 16:233–247

    Article  CAS  PubMed  Google Scholar 

  9. Ribatti D, Vacca A, Rusnati M, Presta M (2007) The discovery of basic fibroblast growth factor/fibroblast growth factor-2 and its role in haematological malignancies. Cytokine Growth Factor Rev 18:327–334

    Article  CAS  PubMed  Google Scholar 

  10. Larsson H, Klint P, Landgren E, Claesson-Welsh L (1999) Fibroblast growth factor receptor-1-mediated endothelial cell proliferation is dependent on the Src homology (SH) 2/SH3 domain-containing adaptor protein Crk. J Biol Chem 274:25726–25734

    Article  CAS  PubMed  Google Scholar 

  11. Bakin AV, Rinehart C, Tomlinson AK, Arteaga CL (2002) p38 mitogen-activated protein kinase is required for TGFbeta-mediated fibroblastic transdifferentiation and cell migration. J Cell Sci 115:3193–3206

    CAS  PubMed  Google Scholar 

  12. Yang Y, Pan X, Lei W, Wang J, Shi J, et al. (2006) Regulation of transforming growth factor-beta 1-induced apoptosis and epithelial-to-mesenchymal transition by protein kinase A and signal transducers and activators of transcription 3. Cancer Res 66:8617–8624

    Article  CAS  PubMed  Google Scholar 

  13. Zuo W, Chen YG (2009) Specific activation of mitogen-activated protein kinase by transforming growth factor-beta receptors in lipid rafts is required for epithelial cell plasticity. Mol Biol Cell 20:1020–1029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ellenrieder V, Hendler SF, Boeck W, Seufferlein T, Menke A, et al. (2001) Transforming growth factor beta1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res 61:4222–4228

    CAS  PubMed  Google Scholar 

  15. Arbeit JM, Olson DC, Hanahan D (1996) Upregulation of fibroblast growth factors and their receptors during multi-stage epidermal carcinogenesis in K14-HPV16 transgenic mice. Oncogene 13:1847–1857

    CAS  PubMed  Google Scholar 

  16. Cancer Genome Atlas Research N (2012) Comprehensive genomic characterization of squamous cell lung cancers. Nature 489:519–525

    Article  Google Scholar 

  17. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG (2015) WHO classification of tumours of the lung, pleura, thymus and heart. IARC, Lyon, 412 p

  18. Schildhaus HU, Heukamp LC, Merkelbach-Bruse S, Riesner K, Schmitz K, et al. (2012) Definition of a fluorescence in-situ hybridization score identifies high- and low-level FGFR1 amplification types in squamous cell lung cancer. Mod Pathol 25:1473–1480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kim HR, Kim DJ, Kang DR, Lee JG, Lim SM, et al. (2013) Fibroblast growth factor receptor 1 gene amplification is associated with poor survival and cigarette smoking dosage in patients with resected squamous cell lung cancer. J Clin Oncol 31:731–737

    Article  PubMed  Google Scholar 

  20. Schultheis AM, Bos M, Schmitz K, Wilsberg L, Binot E, et al. (2014) Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential therapeutic target in small-cell lung cancer. Mod Pathol 27:214–221

    Article  CAS  PubMed  Google Scholar 

  21. Dutt A, Ramos AH, Hammerman PS, Mermel C, Cho J, et al. (2011) Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer. PLoS One 6:e20351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ware KE, Hinz TK, Kleczko E, Singleton KR, Marek LA, et al. (2013) A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop. Oncogenesis 2:e39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yoshimura N, Sano H, Hashiramoto A, Yamada R, Nakajima H, et al. (1998) The expression and localization of fibroblast growth factor-1 (FGF-1) and FGF receptor-1 (FGFR-1) in human breast cancer. Clin Immunol Immunopathol 89:28–34

    Article  CAS  PubMed  Google Scholar 

  24. Wesche J, Haglund K, Haugsten EM (2011) Fibroblast growth factors and their receptors in cancer. Biochem J 437:199–213

    Article  CAS  PubMed  Google Scholar 

  25. Bass AJ, Watanabe H, Mermel CH, Yu S, Perner S, et al. (2009) SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet 41:1238–1242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Behrens C, Lin HY, Lee JJ, Raso MG, Hong WK, et al. (2008) Immunohistochemical expression of basic fibroblast growth factor and fibroblast growth factor receptors 1 and 2 in the pathogenesis of lung cancer. Clin Cancer Res 14:6014–6022

    Article  CAS  PubMed  Google Scholar 

  27. Berger W, Setinek U, Mohr T, Kindas-Mugge I, Vetterlein M, et al. (1999) Evidence for a role of FGF-2 and FGF receptors in the proliferation of non-small cell lung cancer cells. Int J Cancer 83:415–423

    Article  CAS  PubMed  Google Scholar 

  28. Donnem T, Al-Shibli K, Al-Saad S, Busund LT, Bremnes RM (2009) Prognostic impact of fibroblast growth factor 2 in non-small cell lung cancer: coexpression with VEGFR-3 and PDGF-B predicts poor survival. J Thorac Oncol 4:578–585

    Article  PubMed  Google Scholar 

  29. Fischer H, Taylor N, Allerstorfer S, Grusch M, Sonvilla G, et al. (2008) Fibroblast growth factor receptor-mediated signals contribute to the malignant phenotype of non-small cell lung cancer cells: therapeutic implications and synergism with epidermal growth factor receptor inhibition. Mol Cancer Ther 7:3408–3419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kuhn H, Kopff C, Konrad J, Riedel A, Gessner C, et al. (2004) Influence of basic fibroblast growth factor on the proliferation of non-small cell lung cancer cell lines. Lung Cancer 44:167–174

    Article  PubMed  Google Scholar 

  31. Volm M, Koomagi R, Mattern J, Stammler G (1997) Prognostic value of basic fibroblast growth factor and its receptor (FGFR-1) in patients with non-small cell lung carcinomas. Eur J Cancer 33:691–693

    Article  CAS  PubMed  Google Scholar 

  32. Ren M, Hong M, Liu G, Wang H, Patel V, et al. (2013) Novel FGFR inhibitor ponatinib suppresses the growth of non-small cell lung cancer cells overexpressing FGFR1. Oncol Rep 29:2181–2190

    CAS  PubMed  Google Scholar 

  33. O’Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, et al. (2009) AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16:401–412

    Article  PubMed  PubMed Central  Google Scholar 

  34. Marek L, Ware KE, Fritzsche A, Hercule P, Helton WR, et al. (2009) Fibroblast growth factor (FGF) and FGF receptor-mediated autocrine signaling in non-small-cell lung cancer cells. Mol Pharmacol 75:196–207

    Article  CAS  PubMed  Google Scholar 

  35. (2013) ClinicalTrials.gov.

  36. Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, et al. (2008) BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 68:4774–4782

    Article  CAS  PubMed  Google Scholar 

  37. Reck M, Kaiser R, Eschbach C, Stefanic M, Love J, et al. (2011) A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer. Ann Oncol 22:1374–1381

    Article  CAS  PubMed  Google Scholar 

  38. Zhang J, Zhang L, Su X, Li M, Xie L, et al. (2012) Translating the therapeutic potential of AZD4547 in FGFR1-amplified non-small cell lung cancer through the use of patient-derived tumor xenograft models. Clin Cancer Res 18:6658–6667

    Article  CAS  PubMed  Google Scholar 

  39. Chung JH, Rho JK, Xu X, Lee JS, Yoon HI, et al. (2011) Clinical and molecular evidences of epithelial to mesenchymal transition in acquired resistance to EGFR-TKIs. Lung Cancer 73:176–182

    Article  PubMed  Google Scholar 

  40. Grygielewicz P, Dymek B, Bujak A, Gunerka P, Stanczak A, et al. (2014) Epithelial-mesenchymal transition confers resistance to selective FGFR inhibitors in SNU-16 gastric cancer cells. Gastric Cancer

  41. Kim SH, Kim JM, Shin MH, Kim CW, Huang SM, et al. (2012) Correlation of epithelial-mesenchymal transition markers with clinicopathologic parameters in adenocarcinomas and squamous cell carcinoma of the lung. Histol Histopathol 27:581–591

    CAS  PubMed  Google Scholar 

  42. Xiao D, He J (2010) Epithelial mesenchymal transition and lung cancer. J Thorac Dis 2:154–159

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Cihoric N, Savic S, Schneider S, Ackermann I, Bichsel-Naef M, et al. (2014) Prognostic role of FGFR1 amplification in early-stage non-small cell lung cancer. Br J Cancer 110:2914–2922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Goke F, Franzen A, Menon R, Goltz D, Kirsten R, et al. (2012) Rationale for treatment of metastatic squamous cell carcinoma of the lung using fibroblast growth factor receptor inhibitors. Chest 142:1020–1026

    Article  CAS  PubMed  Google Scholar 

  45. Kohler LH, Mireskandari M, Knosel T, Altendorf-Hofmann A, Kunze A, et al. (2012) FGFR1 expression and gene copy numbers in human lung cancer. Virchows Arch 461:49–57

    Article  CAS  PubMed  Google Scholar 

  46. Sasaki H, Shitara M, Yokota K, Hikosaka Y, Moriyama S, et al. (2012) Increased FGFR1 copy number in lung squamous cell carcinomas. Mol Med Rep 5:725–728

    CAS  PubMed  Google Scholar 

  47. Seo AN, Jin Y, Lee HJ, Sun PL, Kim H, et al. (2014) FGFR1 amplification is associated with poor prognosis and smoking in non-small-cell lung cancer. Virchows Arch

  48. Tran TN, Selinger CI, Kohonen-Corish MR, McCaughan BC, Kennedy CW, et al. (2013) Fibroblast growth factor receptor 1 (FGFR1) copy number is an independent prognostic factor in non-small cell lung cancer. Lung Cancer 81:462–467

    Article  PubMed  Google Scholar 

  49. Yang W, Yao YW, Zeng JL, Liang WJ, Wang L, et al. (2014) Prognostic value of FGFR1 gene copy number in patients with non-small cell lung cancer: a meta-analysis. J Thorac Dis 6:803–809

    PubMed  PubMed Central  Google Scholar 

  50. Sequist LV, Bell DW, Lynch TJ, Haber DA (2007) Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol 25:587–595

    Article  CAS  PubMed  Google Scholar 

  51. Slamon DJ (1990) Studies of the HER-2/neu proto-oncogene in human breast cancer. Cancer Investig 8:253

    Article  CAS  Google Scholar 

  52. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, et al. (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182

    Article  CAS  PubMed  Google Scholar 

  53. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, et al. (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712

    Article  CAS  PubMed  Google Scholar 

  54. Gozgit JM, Wong MJ, Moran L, Wardwell S, Mohemmad QK, et al. (2012) Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. Mol Cancer Ther 11:690–699

    Article  CAS  PubMed  Google Scholar 

  55. Popper HH, Ryska A, Timar J, Olszewski W (2014) Molecular testing in lung cancer in the era of precision medicine. Transl Lung Cancer Res 3:291–300

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Wynes MW, Hinz TK, Gao D, Martini M, Marek LA, et al. (2014) FGFR1 mRNA and protein expression, not gene copy number, predict FGFR TKI sensitivity across all lung cancer histologies. Clin Cancer Res 20:3299–3309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors recognize Portuguese Leica Biosystems services and CIMAGO—Research Center for Environment, Genetics and Oncobiology and Centro de Pneumologia for their support.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Vitor Sousa.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

ESM 1

(DOCX 36 kb)

ESM 2

(DOCX 12 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sousa, V., Reis, D., Silva, M. et al. Amplification of FGFR1 gene and expression of FGFR1 protein is found in different histological types of lung carcinoma. Virchows Arch 469, 173–182 (2016). https://doi.org/10.1007/s00428-016-1954-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-016-1954-5

Keywords

Navigation