Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS.
Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS.
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DOI：
10.1038/jid.2013.70
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发表时间：
2013-09
影响因子：
6.5
通讯作者：
Moore, Gudrun E.
中科院分区：
文献类型：
--
作者：
Kinsler, Veronica A.;Thomas, Anna C.;Ishida, Miho;Bulstrode, Neil W.;Loughlin, Sam;Hing, Sandra;Chalker, Jane;McKenzie, Kathryn;Abu-Amero, Sayeda;Slater, Olga;Chanudet, Estelle;Palmer, Rodger;Morrogh, Deborah;Stanier, Philip;Healy, Eugene;Sebire, Neil J.;Moore, Gudrun E.
先天性黑色素细胞痣(CMN)可与神经系统异常和黑色素瘤风险增加相关。在单个CMN样本中已经描述了NRAS、BRAF和TP53的突变；然而，它们在同一对象中的多个CMN的发病机制和相关特征的发展中所起的作用尚不清楚。我们假设，NRAS的单个合子后突变可能导致同一个体的多个CMN，以及黑色素细胞和非黑素细胞中枢神经系统(CNS)损害。对15例患者的55个CMN样本进行定点突变和野生型等位基因的酶消化后测序。NRAS 61密码子的致癌错义突变在12例患者的神经和皮肤组织中发现，而在未受影响的组织和血液中未发现，这与NRAS突变嵌合体现象一致。在10例患者中，突变始终是c.181C>；A，p.Q61K，在2例患者中，突变是c.182a>；G，p.Q61R。5例患者的11例非黑素细胞和黑素细胞中枢神经系统标本均为突变阳性，尽管NRAS在中枢神经系统肿瘤中很少被报道为突变。在两个病例中，杂合性缺失与黑色素瘤的发病有关，这意味着向恶性的多步进展。这些结果表明，在大多数病例中，单个合子后NRAS突变与多发性CMN和相关的神经损害有关。
Congenital melanocytic nevi (CMN) can be associated with neurological abnormalities and an increased risk of melanoma. Mutations in NRAS, BRAF, and Tp53 have been described in individual CMN samples; however, their role in the pathogenesis of multiple CMN within the same subject and development of associated features has not been clear. We hypothesized that a single postzygotic mutation in NRAS could be responsible for multiple CMN in the same individual, as well as for melanocytic and nonmelanocytic central nervous system (CNS) lesions. From 15 patients, 55 samples with multiple CMN were sequenced after site-directed mutagenesis and enzymatic digestion of the wild-type allele. Oncogenic missense mutations in codon 61 of NRAS were found in affected neurological and cutaneous tissues of 12 out of 15 patients, but were absent from unaffected tissues and blood, consistent with NRAS mutation mosaicism. In 10 patients, the mutation was consistently c.181C>A, p.Q61K, and in 2 patients c.182A>G, p.Q61R. All 11 non-melanocytic and melanocytic CNS samples from 5 patients were mutation positive, despite NRAS rarely being reported as mutated in CNS tumors. Loss of heterozygosity was associated with the onset of melanoma in two cases, implying a multistep progression to malignancy. These results suggest that single postzygotic NRAS mutations are responsible for multiple CMN and associated neurological lesions in the majority of cases.
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影响因子：
4.1
作者：
Candeliere, GA;Roughley, PJ;Glorieux, FH
通讯作者：
Glorieux, FH
影响因子：
3.6
作者：
Foster, RD;Williams, ML;Frieden, IJ
通讯作者：
Frieden, IJ
影响因子：
10.3
作者：
Kinsler, V. A.;Chong, W. K.;Atherton, D. J.
通讯作者：
Atherton, D. J.
影响因子：
6.5
作者：
Hacker, Elke;Hayward, Nicholas K.;Whiteman, David C.
通讯作者：
Whiteman, David C.
影响因子：
13.8
作者：
Agero, ALC;Benvenuto-Andrade, C;Marghoob, AA
通讯作者：
Marghoob, AA