Kinsler, VA;
Thomas, AC;
Ishida, M;
Bulstrode, NW;
Loughlin, S;
Hing, S;
Chalker, J;
... Moore, GE; + view all
(2013)
Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS.
Journal of Investigative Dermatology
, 133
(9)
pp. 2229-2236.
10.1038/jid.2013.70.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/jid.2013.70 |
| Publisher version: | http://dx.doi.org/10.1038/jid.2013.70 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http:// creativecommons.org/licenses/by-nc-nd/3.0/. |
| Keywords: | Adolescent, Central Nervous System Neoplasms, Child, Child, Preschool, Female, GTP Phosphohydrolases, Genetic Predisposition to Disease, Hamartoma, Humans, Loss of Heterozygosity, Magnetic Resonance Imaging, Male, Melanosis, Membrane Proteins, Meningeal Neoplasms, Meningioma, Mosaicism, Mutation, Missense, Neurocutaneous Syndromes, Nevus, Pigmented, Prevalence, Risk Factors, Skin Neoplasms, Young Adult, Zygote |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Population, Policy and Practice Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1385331 |
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