Genetic Abnormalities in Large to Giant Congenital Nevi: Beyond NRAS Mutations
Genetic Abnormalities in Large to Giant Congenital Nevi: Beyond NRAS Mutations
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DOI：
10.1016/j.jid.2018.07.045
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发表时间：
2019-04-01
影响因子：
6.5
通讯作者：
Malvehy, Josep
中科院分区：
文献类型：
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作者：
Martins da Silva, Vanessa;Martinez-Barrios, Estefania;Malvehy, Josep
大型和巨型先天性黑素细胞痣（CMN）是罕见的黑素细胞病变，主要由合子后 NRAS 改变引起。分子表征通常集中于 CMN 独特活检样本中的 NRAS 和 BRAF 基因。然而，大/巨型 CMN 可能在不同区域表现出表型差异，并且患者的特征也不同，例如存在多个 CMN 或毛状病变。在此，我们对 21 个大型/巨型 CMN 进行了表征，其中包括 spilus 型痣患者（9/21 例患者，42.8%）。总体而言，使用多基因组和 RNA 测序分析了 53 个新鲜冷冻活检样本，这些样本对应于 40 个大/巨型 CMN 的表型特征区域和 13 个卫星病变。突变筛查显示 76.2% (16/21) 的大型/巨型 CMN 存在突变。 57.1%（12/21）的患者发现NRAS突变，14.3%（3/21）的患者检测到BRAF、KRAS、APC和MET等其他基因突变。 RNA测序显示两名患者的大/巨CMN中存在融合转录本ZEB2-ALK和SOX5-RAF1，没有错义突变。在未受影响的皮肤中未检测到这两种变化，但在受影响皮肤的不同区域中检测到了这两种变化。这些发现表明，除了 NRAS 突变之外，大/巨型 CMN 可能是由不同的分子事件引起的，包括点突变和融合转录本。
Large and giant congenital melanocytic nevi (CMN) are rare melanocytic lesions mostly caused by postzygotic NRAS alteration. Molecular characterization is usually focused on NRAS and BRAF genes in a unique biopsy sample of the CMN. However, large/giant CMN may exhibit phenotypic differences among distinct areas, and patients differ in features such as presence of multiple CMN or spilus-like lesions. Herein, we have characterized a series of 21 large/giant CMN including patients with spilus-type nevi (9/21 patients, 42.8%). Overall, 53 fresh frozen biopsy samples corresponding to 40 phenotypically characterized areas of large/giant CMNs and 13 satellite lesions were analyzed with a multigene panel and RNA sequencing. Mutational screening showed mutations in 76.2% (16/21) of large/giant CMNs. A NRAS mutation was found in 57.1% (12/21) of patients, and mutations in other genes such as BRAF, KRAS, APC, and MET were detected in 14.3% (3/21) of patients. RNA sequencing showed the fusion transcript ZEB2-ALK and SOX5-RAF1 in large/giant CMN from two patients without missense mutations. Both alterations were not detected in unaffected skin and were detected in different areas of affected skin. These findings suggest that large/giant CMN may result from distinct molecular events in addition to NRAS mutations, including point mutations and fusion transcripts.