NRAS Mutation Is the Sole Recurrent Somatic Mutation in Large Congenital Melanocytic Nevi

Abstract

Congenital melanocytic nevus (CMN) is a particular melanocytic in utero proliferation characterized by an increased risk of melanoma transformation during infancy or adulthood. NRAS and BRAF mutations have consistently been reported in CMN samples, but until recently results have been contradictory. We therefore studied a series of large and giant CMNs and compared them with small and medium CMNs using Sanger sequencing, pyrosequencing, high-resolution melting analysis, and mutation enrichment by an enhanced version of ice-COLD-PCR. Large-giant CMNs displayed NRAS mutations in 94.7% of cases (18/19). At that point, the role of additional mutations in CMN pathogenesis had to be investigated. We therefore performed exome sequencing on five specimens of large-giant nevi. The results showed that NRAS mutation was the sole recurrent somatic event found in such melanocytic proliferations. The genetic profile of small-medium CMNs was significantly different, with 70% of cases bearing NRAS mutations and 30% showing BRAF mutations. These findings strongly suggest that NRAS mutations are sufficient to drive melanocytic benign proliferations in utero.

Nras in melanoma: Targeting the undruggable target

“…The frequency of NRAS mutations in medium-sized congenital nevi is 64-70% [39][40][41] and raises to 94.7% in large-giant congenital nevi where it has been recently recognized as the sole recurrent somatic mutation [42]. It has been suggested that NRAS mutations exert stronger growth signals, resulting in the formation of larger nevi than those linked to BRAF mutations [43].…”

Malignant Transformation of a Multi-Operated Divided Nevus of the Eyelids

“…They are almost always mutually exclusive, but mutation heterogeneity has been reported [5]. NRAS mutation is the sole recurrent somatic mutation in large and giant congenital melanocytic nevi, whereas small to medium lesions harbor a BRAF mutation in 30% of the cases [6]. NRAS mutations may allow a greater expansion of melanocytes than BRAF via an inhibition of apoptosis, which would account for its association with larger lesions [7].…”

Untitled

“…Therefore, most cases are a sporadic occurrence. Rare familial forms can be explained by germ cell mosaicism [13]. …”