Genetics of melanocytic nevi

Abstract

Melanocytic nevi are a benign clonal proliferation of cells expressing the melanocytic phenotype, with heterogeneous clinical and molecular characteristics. In this review, we discuss the genetics of nevi by salient nevi subtypes: congenital melanocytic nevi, acquired melanocytic nevi, blue nevi, and Spitz nevi. While the molecular etiology of nevi has been less thoroughly studied than melanoma, it is clear that nevi and melanoma share common driver mutations. Acquired melanocytic nevi harbor oncogenic mutations in BRAF, which is the predominant oncogene associated with melanoma. Congenital melanocytic nevi and blue nevi frequently harbor NRAS mutations and GNAQ mutations, respectively, while Spitz and atypical Spitz tumors often exhibit HRAS and kinase rearrangements. These initial 'driver' mutations are thought to trigger the establishment of benign nevi. After this initial phase of the cell proliferation, a senescence program is executed, causing termination of nevi growth. Only upon the emergence of additional tumorigenic alterations, which may provide an escape from oncogene-induced senescence, can malignant progression occur. Here, we review the current literature on the pathobiology and genetics of nevi in the hope that additional studies of nevi promise to inform our understanding of the transition from benign neoplasm to malignancy.

Keywords: Spitz nevi; acquired melanocytic nevi; blue nevi; congenital melanocytic nevi; genetics.

Figure 1. The RAS Signaling pathways and Nevi

MAPK signaling promotes cell growth and survival and is constitutively active in nevi. RAS family members are activated by receptor tyrosine kinases and signal through effector proteins, including RAF kinases and PI3K. Acquired melanocytic nevi harbor oncogenic mutations in BRAF, which is the predominant oncogene associated with melanoma. Congenital melanocytic nevi, blue nevi, and Spitz nevi frequently harbor NRAS mutations, GNAQ mutations, and HRAS alterations, respectively (Modified from N Engl J Med. 2010 Sep 30;363(14):1352-60 Copyright © (2010) Massachusetts Medical Society. Reprinted with permission.)

Figure 2

Clinical images of nevi. Subtypes of nevi include large CMN (A), medium CMN (B), melanoma arising in CMN (C), intradermal nevus (D), acral junctional nevus (E), dysplastic nevus (F), blue nevus (G), and Spitz nevus (H).