Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas.
Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas.
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DOI：
10.1038/ng.3361
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发表时间：
2015-09
期刊：
影响因子：
30.8
通讯作者：
Halaban R
中科院分区：
文献类型：
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作者：
Krauthammer M;Kong Y;Bacchiocchi A;Evans P;Pornputtapong N;Wu C;McCusker JP;Ma S;Cheng E;Straub R;Serin M;Bosenberg M;Ariyan S;Narayan D;Sznol M;Kluger HM;Mane S;Schlessinger J;Lifton RP;Halaban R
我们报告了213例黑色素瘤的全外显子组测序（WES）。我们的分析建立了NF 1，编码RAS的负调节因子，作为黑色素瘤中第三个最常见的突变基因，仅次于BRAF和NRAS。46%表达野生型BRAF和RAS的黑色素瘤中存在NF 1失活突变，发生在老年患者中，并显示出与其他RAS病基因（特别是RASA 2）共同突变的独特模式。功能研究表明，NF 1抑制导致RAS激活增加，在大多数，但不是所有的黑色素瘤病例。此外，NF1的缺失并不能预测对MEK或ERK抑制剂的敏感性。如通过磷酸化MEK的诱导所见，回弹途径发生在对所研究的药物敏感和耐药的细胞中。我们的结论是，NF 1是一个关键的肿瘤抑制基因在黑色素瘤中丢失，并同时RAS病基因突变可能会增强其在黑色素瘤发生中的作用。
We report on whole-exome sequencing (WES) of 213 melanomas. Our analysis established NF1, encoding a negative regulator of RAS, as the third most frequently mutated gene in melanoma, after BRAF and NRAS. Inactivating NF1 mutations were present in 46% of melanomas expressing wild-type BRAF and RAS, occurred in older patients and showed a distinct pattern of co-mutation with other RASopathy genes, particularly RASA2. Functional studies showed that NF1 suppression led to increased RAS activation in most, but not all, melanoma cases. In addition, loss of NF1 did not predict sensitivity to MEK or ERK inhibitors. The rebound pathway, as seen by the induction of phosphorylated MEK, occurred in cells both sensitive and resistant to the studied drugs. We conclude that NF1 is a key tumor suppressor lost in melanomas, and that concurrent RASopathy gene mutations may enhance its role in melanomagenesis.