Multiple Congenital Melanocytic Nevi and Neurocutaneous Melanosis Are Caused by Postzygotic Mutations in Codon 61 of NRAS

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.

Nras in melanoma: Targeting the undruggable target

“…Recently, different studies have demonstrated that early embryonic/post zygotic somatic mutations in the NRAS gene are implicated in the development of neurocutaneous melanocytosis, a rare congenital disorder, in which affected patients have an increased number of melanocytes in the leptomeninges and the skin, with a large congenital melanocytic nevus usually associated with so-called "satellites" in the vicinity, and childhood melanoma of the central nervous system [46][47][48]. In line with these observations, recently it has been shown that primary melanoma of the CNS in children carries oncogenic mutations in NRAS, unlike primary melanoma of the central nervous system in adults, in which NRAS is not a common driver oncogene [46].…”

Extending the spectrum ofAKT1mosaicism: not just the Proteus syndrome

“…This mirrors the spectrum of severity seen in other known mosaic disorders involving oncogenes and tumour suppressor genes, such as congenital melanocytic naevus syndrome and the PIK3CA ‐related overgrowth spectrum (PROS) disorders 5, 6. Suspected cases of ‘mild’ Proteus syndrome have previously been described in the literature, prior to the discovery of the underlying genetic mutation 7, 8, 9, 10.…”

Next Generation Sequencing and Pediatric Brain Tumors: Detection of Cancer Predisposition Syndromes in Patients and Their Families

“…A growing number of cancer predispositions linked to postzygotic mosaicism might cause a comparably high individual risk as established in familial CPS [11]. However, these patients usually present with a recognizable phenotype.…”