Pathological activation of KIT in metastatic tumors of acral and mucosal melanomas
Pathological activation of KIT in metastatic tumors of acral and mucosal melanomas
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DOI：
10.1002/ijc.24048
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发表时间：
2009-02-15
影响因子：
6.4
通讯作者：
Saida, Toshiaki
中科院分区：
文献类型：
--
作者：
Ashida, Atsuko;Takata, Minoru;Saida, Toshiaki
最近的研究表明，在肢端皮肤和粘膜上的大量黑色素瘤中存在KIT基因异常，这表明酪氨酸激酶抑制剂的治疗效果良好，如伊马替尼。因此，我们检测了4例原发和24例转移性肢端和粘膜黑色素瘤中KIT的表达和突变。免疫组织化学显示13例(48%)肿瘤KIT蛋白呈中等或强表达。序列分析显示，在两个转移瘤中发现了K642E和D820Y突变。实时荧光定量聚合酶链式反应检测4例肿瘤中KIT的扩增，其中1例为K642E。Western印迹分析显示，在13份冷冻保存的标本中，有8份(62%)有(HeKIT)受体的磷酸化。表明该受体在体内频繁的病理性激活。在2例存在KIT突变的肿瘤和1例KIT基因扩增的肿瘤中检测到KIT蛋白的磷酸化。此外，5例未检测到KIT基因异常的肿瘤显示KIT受体磷酸化。在黑色素瘤细胞和间质细胞中，干细胞因子(SCF)的表达提示在这些肿瘤中SCF/KIT自分泌和旁分泌被激活。最后，我们发现舒尼替尼在两个肢端黑色素瘤细胞系中有显著的生长抑制作用；一个携带D820Y突变，另一个显示干细胞因子依赖的KIT激活。这些结果表明KIT在病理上激活了相当数量的肢端和粘膜黑色素瘤的转移性肿瘤。并提出了舒尼替尼对这些黑色素瘤的潜在治疗益处。(C)2008年Wiley-Liss，Inc.
Recent studies showed KIT gene aberrations in a substantial number of melanomas on acral skin and mucosa, suggesting the therapeutic benefit of tyrosine kinase inhibitors', such as imatinib. We therefore examined the expression and mutations of KIT in 4 primary and 24 metastatic acral and mucosal melanomas. Immunohistochemistry revealed moderate or strong KIT protein expression in 13 (48%) tumors. Sequence analysis revealed K642E and D820Y mutations in two metastases. Amplification of KIT was identified by real-time PCR in 4 tumors, including one that had K642E. Western blot analysis showed phosphorylation of(he K IT receptor in 8 (62%) of 13 cryopreserved samples. indicating the frequent pathological activation of the receptor in vivo. Phosphorylation of KIT protein was detected in 2 tumors harboring KIT mutations, as well as in one tumor with KIT gene amplification. Furthermore, 5 tumors without detectable KIT gene aberrations showed phosphorylation of the KIT receptor. Expression of stein cell factor (SCF) in melanoma cells as well as stromal cells suggests SCF/KIT autocrine and paracrine activation in these tumors. Finally, we found significant growth suppressive effects of sunitinib in two acral melanoma cell lines; one harboring the D820Y mutation and one showing SCF-dependent KIT activation. These results show pathological activation of KIT in it substantial number of metastatic tumors of acral and mucosal melanomas. and suggest a potential therapeutic benefit of sunitinib for these melanomas. (c) 2008 Wiley-Liss, Inc.