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C-kit protein expression correlated with activating mutations in KIT gene in oral mucosal melanoma

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Abstract

C-kit is a trans-membrane receptor tyrosine kinase (RTK) encoded by the proto-oncogene KIT located at 4q11-12. Gain-of-function mutations arising to c-kit activation independent of its ligand were observed in various tumors related to germ cells, mast cells, and interstitial cells of Cajal. C-kit also participates in melanocyte development; hence, its involvement in oral mucosal melanoma (OMM) tumorigenesis was investigated. Immunohistochemistry and mutation analysis were performed using 18 cases of human primary OMM. Results revealed 16 cases positive to c-kit protein. Atypical melanocytes expressed c-kit. All in situ components expressed c-kit, but only four cases exhibited intense expression in the invasive component. Missense mutations were observed in four cases, and two of those correlated with increased protein expression. C-kit expression in atypical melanocytes suggests the role of c-kit in the early stage of OMM tumorigenesis. C-kit protein expression correlated with activating mutations indicating the pertinent role of the proto-oncogene KIT in the tumorigenesis of OMM.

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References

  1. Alexeev V, Yoon K (2006) Distinctive role of the cKit receptor tyrosine kinase signaling in mammalian melanocytes. J Invest Dermatol 126:1102–1110

    Article  PubMed  CAS  Google Scholar 

  2. Alexis JB, Martinez AE, Lutzky J (2005) An immunohistochemical evaluation of c-kit (CD-117) expression in malignant melanoma, and results of imatinib mesylate (Gleevec) therapy in three patients. Melanoma Res 15:283–285

    Article  PubMed  CAS  Google Scholar 

  3. All-Ericsson C, Girnita L, Muller-Brunotte A, Brodin B, Seregard S, Ostman A, Larsson O (2004) c-Kit-dependent growth of uveal melanoma cells: a potential therapeutic target? Invest Ophthalmol Vis Sci 45:2075–2082

    Article  PubMed  Google Scholar 

  4. Andersson J, Bumming P, Meis-Kindblom JM, Sihto H, Nupponen N, Joensuu H, Oden A, Gustavsson B, Kindblom LG, Nilsson B (2006) Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis. Gastroenterology 130:1573–1581

    Article  PubMed  CAS  Google Scholar 

  5. Barker BF, Carpenter WM, Daniels TE, Kahn MA, Leider AS, Lozada-Nur F, Lynch DP, Melrose R, Merrell P, Morton T, Peters E, Regezi JA, Richards SD, Rick GM, Rohrer MD, Slater L, Stewart JC, Tomich CE, Vickers RA, Wood NK, Young SK (1997) Oral mucosal melanomas: the WESTOP Banff workshop proceedings. Western Society of Teachers of Oral Pathology. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 83:672–679

    Article  PubMed  CAS  Google Scholar 

  6. Becker JC, Brocker EB, Schadendorf D, Ugurel S (2007) Imatinib in melanoma: a selective treatment option based on KIT mutation status? J Clin Oncol 25:e9

    Article  PubMed  Google Scholar 

  7. Corless CL, McGreevey L, Haley A, Town A, Heinrich MC (2002) KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am J Pathol 160:1567–1572

    PubMed  CAS  Google Scholar 

  8. Curtin JA, Busam K, Pinkel D, Bastian BC (2006) Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 24:4340–4346

    Article  PubMed  CAS  Google Scholar 

  9. Daum O, Grossmann P, Vanecek T, Sima R, Mukensnabl P, Michal M (2007) Diagnostic morphological features of PDGFRA-mutated gastrointestinal stromal tumors: molecular genetic and histologic analysis of 60 cases of gastric gastrointestinal stromal tumors. Ann Diagn Pathol 11:27–33

    Article  PubMed  Google Scholar 

  10. Do I, Araujo ES, Kalil RK, Bacchini P, Bertoni F, Unni KK, Park YK (2007) Protein expression of KIT and gene mutation of c-kit and PDGFRs in Ewing sarcomas. Pathol Res Pract 203:127–134

    Article  PubMed  CAS  Google Scholar 

  11. Fiorentini G, Rossi S, Lanzanova G, Biancalani M, Palomba A, Bernardeschi P, Dentico P, De Giorgi U (2003) Tyrosine kinase inhibitor imatinib mesylate as anticancer agent for advanced ocular melanoma expressing immunohistochemical C-KIT (CD 117): preliminary results of a compassionate use clinical trial. J Exp Clin Cancer Res 22:17–20

    PubMed  CAS  Google Scholar 

  12. Flaherty KT (2006) Chemotherapy and targeted therapy combinations in advanced melanoma. Clin Cancer Res 12:2366s–2370s

    Article  PubMed  CAS  Google Scholar 

  13. Hicks MJ, Flaitz CM (2000) Oral mucosal melanoma: epidemiology and pathobiology. Oral Oncol 36:152–169

    Article  PubMed  CAS  Google Scholar 

  14. Hirota S, Ohashi A, Nishida T, Isozaki K, Kinoshita K, Shinomura Y, Kitamura Y (2003) Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterology 125:660–667

    Article  PubMed  CAS  Google Scholar 

  15. Isozaki K, Terris B, Belghiti J, Schiffmann S, Hirota S, Vanderwinden JM (2000) Germline-activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors. Am J Pathol 157:1581–1585

    PubMed  CAS  Google Scholar 

  16. Ivan D, Niveiro M, Diwan AH, Eton O, Kim KB, Lacey C, Gonzalez C, Prieto VG (2006) Analysis of protein tyrosine kinases expression in the melanoma metastases of patients treated with Imatinib Mesylate (STI571, Gleevec). J Cutan Pathol 33:280–285

    Article  PubMed  Google Scholar 

  17. Jin T, Nakatani H, Taguchi T, Nakano T, Okabayashi T, Sugimoto T, Kobayashi M, Araki K (2006) STI571 (Glivec) suppresses the expression of vascular endothelial growth factor in the gastrointestinal stromal tumor cell line, GIST-T1. World J Gastroenterol 12:703–708

    PubMed  CAS  Google Scholar 

  18. Kang DY, Park CK, Choi JS, Jin SY, Kim HJ, Joo M, Kang MS, Moon WS, Yun KJ, Yu ES, Kang H, Kim KM (2007) Multiple gastrointestinal stromal tumors: clinicopathologic and genetic analysis of 12 patients. Am J Surg Pathol 31:224–232

    Article  PubMed  Google Scholar 

  19. Kinoshita K, Isozaki K, Hirota S, Nishida T, Chen H, Nakahara M, Nagasawa Y, Ohashi A, Shinomura Y, Kitamura Y, Matsuzawa Y (2003) C-kit gene mutation at exon 17 or 13 is very rare in sporadic gastrointestinal stromal tumors. J Gastroenterol Hepatol 18:147–151

    Article  PubMed  CAS  Google Scholar 

  20. Lefevre G, Glotin AL, Calipel A, Mouriaux F, Tran T, Kherrouche Z, Maurage CA, Auclair C, Mascarelli F (2004) Roles of stem cell factor/c-Kit and effects of Glivec/STI571 in human uveal melanoma cell tumorigenesis. J Biol Chem 279:31769–31779

    Article  PubMed  CAS  Google Scholar 

  21. Lennartsson J, Blume-Jensen P, Hermanson M, Ponten E, Carlberg M, Ronnstrand L (1999) Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction. Oncogene 18:5546–5553

    Article  PubMed  CAS  Google Scholar 

  22. Leslie MC, Bar-Eli M (2005) Regulation of gene expression in melanoma: new approaches for treatment. J Cell Biochem 94:25–38

    Article  PubMed  CAS  Google Scholar 

  23. Lin SC, Liu CL, Wang TI, Chang WS, Tzen CY, Huang MJ (2006) Clinical implications of C-kit gene mutation in patients with large gastrointestinal stromal tumors. J Gastroenterol Hepatol 21:1604–1608

    Article  PubMed  CAS  Google Scholar 

  24. Litz J, Krystal GW (2006) Imatinib inhibits c-Kit-induced hypoxia-inducible factor-1alpha activity and vascular endothelial growth factor expression in small cell lung cancer cells. Mol Cancer Ther 5:1415–1422

    Article  PubMed  CAS  Google Scholar 

  25. Litz J, Sakuntala Warshamana-Greene G, Sulanke G, Lipson KE, Krystal GW (2004) The multi-targeted kinase inhibitor SU5416 inhibits small cell lung cancer growth and angiogenesis, in part by blocking Kit-mediated VEGF expression. Lung Cancer 46:283–91

    Article  PubMed  Google Scholar 

  26. Lux ML, Rubin BP, Biase TL, Chen CJ, Maclure T, Demetri G, Xiao S, Singer S, Fletcher CD, Fletcher JA (2000) KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. Am J Pathol 156:791–795

    PubMed  CAS  Google Scholar 

  27. Montone KT, van Belle P, Elenitsas R, Elder DE (1997) Proto-oncogene c-kit expression in malignant melanoma: protein loss with tumor progression. Mod Pathol 10:939–944

    PubMed  CAS  Google Scholar 

  28. Nagatsuka H, Rivera RS, Gunduz M, Lee YJ, Tamamura R, Gunduz E, Naito I, Sado Y, Nagai N (2005) Immunolocalization and distribution patterns of type IV collagen alpha chains in oral mucosal melanoma. Virchows Arch 447:710–716

    Article  PubMed  CAS  Google Scholar 

  29. Natali PG, Nicotra MR, Winkler AB, Cavaliere R, Bigotti A, Ullrich A (1992) Progression of human cutaneous melanoma is associated with loss of expression of c-kit proto-oncogene receptor. Int J Cancer 52:197–201

    Article  PubMed  CAS  Google Scholar 

  30. Ohashi A, Funasaka Y, Ueda M, Ichihashi M (1996) c-KIT receptor expression in cutaneous malignant melanoma and benign melanotic naevi. Melanoma Res 6:25–30

    Article  PubMed  CAS  Google Scholar 

  31. Pache M, Glatz K, Bosch D, Dirnhofer S, Mirlacher M, Simon R, Schraml P, Rufle A, Flammer J, Sauter G, Meyer P (2003) Sequence analysis and high-throughput immunohistochemical profiling of KIT (CD 117) expression in uveal melanoma using tissue microarrays. Virchows Arch 443:741–744

    Article  PubMed  CAS  Google Scholar 

  32. Puputti M, Tynninen O, Sihto H, Blom T, Maenpaa H, Isola J, Paetau A, Joensuu H, Nupponen NN (2006) Amplification of KIT, PDGFRA, VEGFR2, and EGFR in gliomas. Mol Cancer Res 4:927–934

    Article  PubMed  CAS  Google Scholar 

  33. Rapidis AD, Apostolidis C, Vilos G, Valsamis S (2003) Primary malignant melanoma of the oral mucosa. J Oral Maxillofac Surg 61:1132–1139

    Article  PubMed  Google Scholar 

  34. Shen SS, Zhang PS, Eton O, Prieto VG (2003) Analysis of protein tyrosine kinase expression in melanocytic lesions by tissue array. J Cutan Pathol 30:539–547

    Article  PubMed  Google Scholar 

  35. Stefanou D, Batistatou A, Zioga A, Arkoumani E, Papachristou DJ, Agnantis NJ (2004) Immunohistochemical expression of vascular endothelial growth factor (VEGF) and C-KIT in cutaneous melanocytic lesions. Int J Surg Pathol 12:133–138

    Article  PubMed  CAS  Google Scholar 

  36. Ugurel S, Hildenbrand R, Zimpfer A, La Rosee P, Paschka P, Sucker A, Keikavoussi P, Becker JC, Rittgen W, Hochhaus A, Schadendorf D (2005) Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer 92:1398–1405

    Article  PubMed  CAS  Google Scholar 

  37. Wardelmann E, Losen I, Hans V, Neidt I, Speidel N, Bierhoff E, Heinicke T, Pietsch T, Buttner R, Merkelbach-Bruse S (2003) Deletion of Trp-557 and Lys-558 in the juxtamembrane domain of the c-kit protooncogene is associated with metastatic behavior of gastrointestinal stromal tumors. Int J Cancer 106:887–895

    Article  PubMed  CAS  Google Scholar 

  38. Willmore C, Holden JA, Zhou L, Tripp S, Wittwer CT, Layfield LJ (2004) Detection of c-kit-activating mutations in gastrointestinal stromal tumors by high-resolution amplicon melting analysis. Am J Clin Pathol 122:206–216

    Article  PubMed  CAS  Google Scholar 

  39. Willmore-Payne C, Holden JA, Tripp S, Layfield LJ (2005) Human malignant melanoma: detection of BRAF- and c-kit-activating mutations by high-resolution amplicon melting analysis. Hum Pathol 36:486–493

    Article  PubMed  CAS  Google Scholar 

  40. Wyman K, Atkins MB, Prieto V, Eton O, McDermott DF, Hubbard F, Byrnes C, Sanders K, Sosman JA (2006) Multicenter phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer 106:2005–2011

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology (B17406027, C19592109). The authors would also like to thank Ms. Kazuko Funakoshi for her technical expertise. The experiments complied with the current laws of Japan.

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Authors and Affiliations

  1. Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama, 700-8525, Japan

    Rosario S. Rivera, Hitoshi Nagatsuka, Mehmet Gunduz, Beyhan Cengiz, Esra Gunduz, Hidetsugu Tsujigiwa, Ryo Tamamura & Noriyuki Nagai

  2. College of Dentistry, University of the East, Manila, Philippines

    Rosario S. Rivera

  3. Department of Oral Pathology, Oral Medicine and Periodontology, Faculty of Dentistry, University of Malaya, Kuala Lampur, Malaysia

    Chong Huat Siar

  4. Unit of Stomatology, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur, Malaysia

    Kok Ng Han

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  1. Rosario S. Rivera
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  2. Hitoshi Nagatsuka
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  9. Kok Ng Han
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  10. Noriyuki Nagai
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Correspondence to Hitoshi Nagatsuka.

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Rivera, R.S., Nagatsuka, H., Gunduz, M. et al. C-kit protein expression correlated with activating mutations in KIT gene in oral mucosal melanoma. Virchows Arch 452, 27–32 (2008). https://doi.org/10.1007/s00428-007-0524-2

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  • DOI: https://doi.org/10.1007/s00428-007-0524-2

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