Molecular pathogenesis of malignant melanoma: a different perspective from the studies of melanocytic nevus and acral melanoma
Molecular pathogenesis of malignant melanoma: a different perspective from the studies of melanocytic nevus and acral melanoma
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DOI：
10.1111/j.1755-148x.2009.00645.x
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发表时间：
2010-02
影响因子：
4.3
通讯作者：
M. Takata;H. Murata;T. Saida
中科院分区：
文献类型：
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作者：
M. Takata;H. Murata;T. Saida
黑色素瘤进展的Clark模型强调从良性黑色素细胞痣开始经发育不良痣到黑色素瘤的一系列组织病理学变化。黑色素瘤发生和进展的遗传基础的几个模型是基于这种Clark的多步骤模型，并预测BRAF突变的获得可以是黑色素细胞瘤形成的创始事件。然而，我们最近的研究挑战了这一观点，显示黑素细胞痣中BRAF突变的多克隆性。此外，它表明，许多黑色素瘤，包括肢端和粘膜黑色素瘤，产生从头，而不是从黑色素细胞痣。虽然BRAF基因突变在白人中普遍存在的非慢性日光损伤皮肤上的黑素瘤中频繁发生，但肢端和粘膜黑素瘤具有KIT基因突变以及细胞周期蛋白D1或细胞周期蛋白依赖性激酶4基因扩增。在外观正常的“野黑素细胞”中检测到细胞周期蛋白D1基因的扩增，这代表了肢端黑色素瘤的潜伏进展阶段，该阶段先于表皮中的非典型黑素细胞增殖阶段。基于这些观察结果，我们提出了一种黑色素瘤的替代遗传进展模型。
The Clark model for melanoma progression emphasizes a series of histopathological changes beginning from benign melanocytic nevus to melanoma via dysplastic nevus. Several models of the genetic basis of melanoma development and progression are based on this Clark’s multi‐step model, and predict that the acquisition of a BRAF mutation can be a founder event in melanocytic neoplasia. However, our recent investigations have challenged this view, showing the polyclonality of BRAF mutations in melanocytic nevi. Furthermore, it is suggested that many melanomas, including acral and mucosal melanomas, arise de novo, not from melanocytic nevus. While mutations of the BRAF gene are frequent in melanomas on non‐chronic sun damaged skin which are prevalent in Caucasians, acral and mucosal melanomas harbor mutations of the KIT gene as well as the amplifications of cyclin D1 or cyclin‐dependent kinase 4 gene. Amplifications of the cyclin D1 gene are detected in normal‐looking ‘field melanocytes’, which represent a latent progression phase of acral melanoma that precedes the stage of atypical melanocyte proliferation in the epidermis. Based on these observations, we propose an alternative genetic progression model for melanoma.