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Targeting c-KIT, PDGFR in cancer of unknown primary: a screening study for molecular markers of benefit

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Abstract

Aims

In view of available targeted therapies, we investigated the presence of c-kit, PDGFR gene mutations and protein expression in cancer of unknown primary (CUP) in order to study their contribution in pathogenesis, their prognostic value and potential as therapeutic targets.

Methods

Mutations in hot spots c-kit exon 11 and PDGFR exons 12 and 18 were studied in paraffin-embedded tumour samples from 50 patients with CUP by means of PCR-based single-strand conformational polymorphism and protein expression by means of streptavidin-biotin immunoperoxidase assays. Molecular markers were screened for possible correlations with patient outcome.

Results

No shifted band was detected in any of the polyacrylamide gel electrophoreses, indicating absence of c-kit exon 11 and PDGFR exon 12, 18 mutations. Immunohistochemical analysis in 37 tumours revealed positive membranous CD117 expression in 30 samples (81%) of which five exhibited strong (+3), four moderate (+2) and 21 weak (+1) staining. PDGFRa protein staining was seen in 15 out of 30 (50%) cases, mostly weak (13) and rarely moderate (1) or strong (1). The expression of KIT or PDGFRa protein did not correlate with the clinical outcome of the patients in our cohort.

Conclusions

In a moderate-sized CUP patient cohort, KIT or PDGFRa protein overexpression is rare, does not have gross prognostic significance for survival and is not associated with presence of activating mutations.

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References

  • Buchdunger E, Cioffi CL, Law N et al (2000) Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295(1):139–145

    PubMed  CAS  Google Scholar 

  • Burger H, den Bakker MA, Stoter G, Verweij J, Nooter K (2003) Lack of c-kit exon 11 activating mutations in c-KIT/CD117-positive SCLC tumour specimens. Eur J Cancer 39(6):793–799

    Article  PubMed  CAS  Google Scholar 

  • Carvalho I, Milanezi F, Martins A, Reis RM, Schmitt F (2005) Overexpression of platelet-derived growth factor receptor alpha in breast cancer is associated with tumour progression. Breast Cancer Res 7(5):R788–R795

    Article  PubMed  CAS  Google Scholar 

  • Claesson-Welsh L, Eriksson A, Westermark B, Heldin CH (1989) cDNA cloning and expression of the human A-type platelet-derived growth factor (PDGF) receptor establishes structural similarity to the B-type PDGF receptor. Proc Natl Acad Sci USA 86(13):4917–4921

    Article  PubMed  CAS  Google Scholar 

  • Corless CL, Fletcher JA, Heinrich MC (2004) Biology of gastrointestinal stromal tumors. J Clin Oncol 22(18):3813–3825

    Article  PubMed  CAS  Google Scholar 

  • Corless CL, Schroeder A, Griffith D et al (2005) PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 23(23):5357–5364

    Article  PubMed  CAS  Google Scholar 

  • Debiec-Rychter M, Dumez H, Judson I et al (2004) EORTC Soft Tissue and Bone Sarcoma Group. Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 40(5):689–695

    Article  PubMed  CAS  Google Scholar 

  • Demetri GD, von Mehren M, Blanke CD et al (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347(7):472–480

    Article  PubMed  CAS  Google Scholar 

  • Demetri GD, van Oosterom AT, Garrett CR et al (2006) Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368(9544):1329–1338

    Article  PubMed  CAS  Google Scholar 

  • de Silva CM, Reid R (2003) Gastrointestinal stromal tumors (GIST): C-kit mutations, CD117 expression, differential diagnosis and targeted cancer therapy with Imatinib. Pathol Oncol Res 9(1):13–19

    Article  PubMed  Google Scholar 

  • Dova L, Pentheroudakis G, Georgiou I et al (2007) Global profiling of EGFR gene mutation, amplification, regulation and tissue protein expression in unknown primary carcinomas: to target or not to target? Clin Exp Metastases 24(2):79–86

    Article  CAS  Google Scholar 

  • Gomes AL, Bardales RH, Milanezi F, Reis RM, Schmitt F (2007) Molecular analysis of c-Kit and PDGFRA in GISTs diagnosed by EUS. Am J Clin Pathol 127(1):1–8

    Google Scholar 

  • Heinrich MC, Corless CL, Duensing A et al (2003a) PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299(5607):708–710

    Article  PubMed  CAS  Google Scholar 

  • Heinrich MC, Corless CL, Demetri GD et al (2003b) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21(23):4342–4349

    Article  PubMed  CAS  Google Scholar 

  • Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79(4):1283–1316

    PubMed  CAS  Google Scholar 

  • Hirota S, Isozaki K, Moriyama Y et al (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279(5350):577–580

    Article  PubMed  CAS  Google Scholar 

  • Hirota S, Ohashi A, Nishida T et al (2003) Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterology 125(3):660–667

    Article  PubMed  CAS  Google Scholar 

  • Johnson BE, Fischer T, Fischer B et al (2003) Phase II study of imatinib in patients with small cell lung cancer. Clin Cancer Res 9(16 Pt 1):5880–5887

    PubMed  CAS  Google Scholar 

  • Kazlauskas A, Cooper JA (1989) Autophosphorylation of the PDGF receptor in the kinase insert region regulates interactions with cell proteins. Cell 58(6):1121–1133

    Article  PubMed  CAS  Google Scholar 

  • Kitamura Y, Hirotab S (2004) Kit as a human oncogenic tyrosine kinase. Cell Mol Life Sci 61(23):2924–2931

    Article  PubMed  CAS  Google Scholar 

  • Langerak AW, De Laat PA, Van Der Linden-Van Beurden CA et al (1996) Expression of platelet-derived growth factor (PDGF) and PDGF receptors in human malignant mesothelioma in vitro and in vivo. J Pathol 178(2):151–160

    Article  PubMed  CAS  Google Scholar 

  • Liegl B, Leithner A, Bauernhofer T et al (2006) Immunohistochemical and mutational analysis of PDGF and PDGFR in desmoid tumours: is there a role for tyrosine kinase inhibitors in c-kit-negative desmoid tumours? Histopathology 49(6):576–581

    Article  PubMed  CAS  Google Scholar 

  • Marx J. (2005) Cancer. Encouraging results for second-generation antiangiogenesis drugs. Science 308(5726):1248–1249

    Article  PubMed  CAS  Google Scholar 

  • Motzer RJ, Rini BI, Bukowski RM et al (2006a) Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295(21):2516–2524

    Article  PubMed  CAS  Google Scholar 

  • Motzer RJ, Michaelson MD, Redman BG et al (2006a) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24(1):16–24

    Article  PubMed  CAS  Google Scholar 

  • Ongkeko WM, Altuna X, Weisman RA, Wang-Rodriguez J (2005) Expression of protein tyrosine kinases in head and neck squamous cell carcinomas. Am J Clin Pathol 124(1):71–76

    Article  PubMed  CAS  Google Scholar 

  • Pentheroudakis G, Pavlidis N (2006) Perspectives for targeted therapy in cancer of unknown primary site. Cancer Treat Rev 32:637–644

    Article  PubMed  CAS  Google Scholar 

  • Pentheroudakis G, Briasoulis E, Pavlidis N (2007) Cancer of unknown primary site: missing primary or missing biology? Oncologist 12(4):418–425

    Article  PubMed  CAS  Google Scholar 

  • Peterson MR, Piao Z, Weidner N, Yi ES (2006) Strong PDGFRA positivity is seen in GISTs but not in other intra-abdominal mesenchymal tumors: immunohistochemical and mutational analyses. Appl Immunohistochem Mol Morphol 14(4):390–6

    Article  PubMed  CAS  Google Scholar 

  • Rashid A, Hess KR, Lenzi R, et al (2005) Overexpression and prevalence of molecular markers in patients with cancer of unknown primary (CUP). Journal of Clinical Oncology 2005, ASCO Annual Meeting Proceedings, Vol 23, No 16S, Part 1, June 1 Supplement, Abstract number 9683

  • Rubin BP, Singer S, Tsao C et al (2001) KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 61(22):8118–8121

    PubMed  CAS  Google Scholar 

  • Shih AH, Holland EC (2006) Platelet-derived growth factor (PDGF) and glial tumorigenesis. Cancer Lett 232(2):139–147

    Article  PubMed  CAS  Google Scholar 

  • Sihto H, Sarlomo-Rikala M, Tynninen O et al (2005) KIT and platelet-derived growth factor receptor alpha tyrosine kinase gene mutations and KIT amplifications in human solid tumors. J Clin Oncol 23(1):49–57

    Article  PubMed  CAS  Google Scholar 

  • Sulzbacher I, Birner P, Träxler M, Marberger M, Haitel A (2003a) Expression of platelet-derived growth factor-alpha alpha receptor is associated with tumor progression in clear cell renal cell carcinoma. Am J Clin Pathol 120(1):107–112

    Article  PubMed  CAS  Google Scholar 

  • Sulzbacher I, Birner P, Trieb K, Träxler M, Lang S, Chott A (2003b) Expression of platelet-derived growth factor-AA is associated with tumor progression in osteosarcoma. Mod Pathol 16(1):66–71

    Article  PubMed  Google Scholar 

  • Ugurel S, Hildenbrand R, Zimpfer A et al (2005) Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer 92(8):1398–1405

    Article  PubMed  CAS  Google Scholar 

  • Went PT, Dirnhofer S, Bundi M et al (2004) Prevalence of KIT expression in human tumors. J Clin Oncol 22(22):4514–4522

    Article  PubMed  CAS  Google Scholar 

  • Wilczynski SP, Chen YY, Chen W, Howell SB, Shively JE, Alberts DS (2005) Expression and mutational analysis of tyrosine kinase receptors c-kit, PDGFRalpha, and PDGFRbeta in ovarian cancers. Hum Pathol 36(3):242–249

    Article  PubMed  CAS  Google Scholar 

  • Yarden Y, Kuang WJ, Yang-Feng T et al (1987) Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J 6(11):3341–3351

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Hematological Laboratory, Molecular Biology Unit, Ioannina University Hospital, Ioannina, Greece

    L. Dova & G. Vartholomatos

  2. Department of Medical Oncology, Ioannina University Hospital, Panepistimiou Avenue, 45110, Ioannina, Greece

    G. Pentheroudakis, V. Golfinopoulos & N. Pavlidis

  3. Department of Pathology, Ioannina University Hospital, Ioannina, Greece

    V. Malamou-Mitsi

  4. Genetics Unit, Department of Obstetrics and Gynaecology, Ioannina University Hospital, Ioannina, Greece

    I. Georgiou

  5. Department of Pathology, Chatzikosta General Hospital, Ioannina, Greece

    A. Ntemou

  6. Department of Medical Oncology, Papageorgiou General Hospital, Medical School, Aristotle University of Thessaloniki, Macedonia, Greece

    G. Fountzilas

Authors
  1. L. Dova
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  2. G. Pentheroudakis
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  3. V. Golfinopoulos
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  4. V. Malamou-Mitsi
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  5. I. Georgiou
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  6. G. Vartholomatos
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  7. A. Ntemou
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  8. G. Fountzilas
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  9. N. Pavlidis
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Corresponding author

Correspondence to N. Pavlidis.

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Dova, L., Pentheroudakis, G., Golfinopoulos, V. et al. Targeting c-KIT, PDGFR in cancer of unknown primary: a screening study for molecular markers of benefit. J Cancer Res Clin Oncol 134, 697–704 (2008). https://doi.org/10.1007/s00432-007-0341-7

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  • DOI: https://doi.org/10.1007/s00432-007-0341-7

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