Genotypic and Gene Expression Studies in Congenital Melanocytic Nevi: Insight into Initial Steps of Melanotumorigenesis
Genotypic and Gene Expression Studies in Congenital Melanocytic Nevi: Insight into Initial Steps of Melanotumorigenesis
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DOI：
10.1038/jid.2008.203
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发表时间：
2009-01-01
影响因子：
6.5
通讯作者：
Heimann, Pierre
中科院分区：
文献类型：
--
作者：
Dessars, Barbara;De Raeve, Linda E.;Heimann, Pierre
大的先天性黑色素细胞痣（CMNs）据说有更高的倾向，恶性转化相比，后天痣。因此，它们代表了一个很好的模型，用于研究黑色素瘤发生的初始步骤。我们已经进行了基因型（核型，荧光原位杂交和突变分析）和差异表达的研究中（n=3）和大（n=24）CMN的大队列。染色体异常是罕见的，单一的，一个功能可能反映了良性病变。突变筛查显示，在我们的系列中NRAS突变频率较高（19/27例，70%），而BRAF突变不太常见（4/27例，15%）。差异未显示细胞过程（如细胞增殖、细胞迁移/侵袭、血管生成、细胞凋亡和免疫/炎症反应）的显著改变。然而，观察到色素沉着相关基因的显著下调和在DNA保护中起作用的基因的上调。最后，我们的微阵列显示介导癌症化疗耐药性的基因上调。由于色素沉着机制的改变可以引发氧化损伤，参与维持DNA完整性的基因表达增加可能反映了痣细胞自我保护免受细胞应激的能力。此外，观察到的变化与化疗耐药性可能部分解释了众所周知的化疗无效的恶性黑色素瘤。
Large congenital melanocytic nevi (CMNs) are said to have a higher propensity to malignant transformation compared with acquired nevi. Thus, they represent a good model for studying initial steps of melanotumorigenesis. We have performed genotypic (karyotype, fluorescence in situ hybridization, and mutational analyses) and differential expression studies on a large cohort of medium (n=3) and large (n=24) CMN. Chromosomal abnormalities were rare and single, a feature probably reflecting the benignity of these lesions. Mutational screening showed a high frequency of NRAS mutations in our series (19/27 cases, 70%), whereas BRAF mutations were less common (4/27 cases, 15%). Differential did not show significant alterations of cellular processes such as cell proliferation, cell migration/invasion, angiogenesis, apoptosis, and immune/inflammatory responses. However, significant downregulation of genes involved in pigmentation and upregulation of genes playing a role in DNA protection were observed. Lastly, our microarrays displayed upregulation of genes mediating chemoresistance in cancer. As alteration of pigmentation mechanisms can trigger oxidative damage, increased expression of genes involved in maintenance of DNA integrity might reflect the ability of nevocytic cells to self-protect against cellular stress. Furthermore, the observed alterations linked to chemoresistance might partially account for the well-known inefficacy of chemotherapy in malignant melanoma.