犬隻黑色素瘤和c-kit致癌基因之臨床相關性研究

潘秀莉

doi:10.6342/NTU.2011.02186

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犬隻黑色素瘤和c-kit致癌基因之臨床相關性研究

Clinical relevance of canine melanomas and c-kit oncogene

潘秀莉 , Masters　　Advisor：葉力森　　Co-advisor ：廖泰慶

繁體中文 DOI： 10.6342/NTU.2011.02186

犬黑色素瘤； KIT蛋白； c-kit致癌基因；標靶治療； canine melanoma ； KIT ； c-kit oncogene ； target therapy

Abstract │ Reference (80) │ Altmetrics

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Melanoma is a malignant tumor in dogs, and can be found associated with skin, nail bed or oral cavity. The etiology of melanoma in dogs is largely unknown. Systemic chemotherapy for malignant melanoma in the dog has not shown any significant benefit. Coarse fraction radiotherapy has only been used for local control. However, most dogs with malignant disease succumb to systemic spread. Several novel therapeutic modalities have been investigated. These include methods of gene therapy, target therapy, etc. KIT is a receptor tyrosine kinase, and SCF(stem cell factor) is the ligand for KIT. SCF is capable of binding to KIT resulting in activation of intracellular domain and initiation of multiple downstream signal transductions. Mutation or overexpression of KIT can transform indolent tumors to aggressive tumors in vivo. In human, KIT have long been hypothesized to play key roles in melanoma development, especially in mucosal and acral melanomas. Importantly, expression of mutation was then found to correlate with the sensitivity of target therapy. In this study, there were 49 cases of canine melanomas collected from National Taiwan University Animal Hospital. KIT protein expression was determined by immunohistochemistry, and KIT gene mutations were analysed by PCR amplification and electrophoresis. Then we discussed the clinical relevance of canine melanomas and KIT, such as the location, prognosis, etc., and evaluate the possibility of the target therapy in canine melanoma. The average age of these 49 cases was 12±2.9 years old. In 40 slides of immunohistiochemistry, all the samples presented positive, then 40%(16/40) for weak positive and 60%(24/40) for strong positive. There were no statistical significances between KIT expression and canine melanoma location, local recurrence rate or survival times. However, these was statistical significance between KIT expression and canine melanoma metastasis rate. The stronger KIT expression, the higher metastasis rate was noted. In the PCR and electrophoresis results, there was no ITD (internal tandem duplications) found in exon 11 of c-kit. Otherwise, a C1743T silence mutation of exon 11 of c-kit was revealed in five canine oral mucosal melanomas by sequencing, and one of the five sample existed a T1736C in-frame missense (L579P) mutation. There is the possibility of target therapy for canine melanoma in the future.

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1. Alexeev V, and Yoon K. Distinctive role of the cKit receptor tyrosine kinase signaling in mammalian melanocytes. J Invest Dermatol 126: 1102-1110, 2006.
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2. Alexis JB, Martinez AE, and Lutzky J. 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, 2005.
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3. Antonescu CR, Busam KJ, Francone TD, Wong GC, Guo T, Agaram NP, Besmer P, Jungbluth A, Gimbel M, Chen CT, Veach D, Clarkson BD, Paty PB, and Weiser MR. L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition. Int J Cancer 121: 257-264, 2007.
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5. Ashida A, Takata M, Murata H, Kido K, and Saida T. Pathological activation of KIT in metastatic tumors of acral and mucosal melanomas. Int J Cancer 124: 862-868, 2009.
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7. Bergman PJ. Canine oral melanoma. Clin Tech Small Anim Pract 22: 55-60, 2007.
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