Genomic Characterization of Dysplastic Nevi Unveils Implications for Diagnosis of Melanoma

Abstract

A well-defined risk factor and precursor for cutaneous melanoma is the dysplastic nevus. These benign tumors represent clonal hyperproliferation of melanocytes that are in a senescent-like state, but with occasional malignant transformation events. To portray the mutational repertoire of dysplastic nevi in patients with the dysplastic nevus syndrome and to determine the discriminatory profiles of melanocytic nevi (including dysplastic nevi) from melanoma, we sequenced exomes of melanocytic nevi including dysplastic nevi (n = 19), followed by a targeted gene panel (785 genes) characterization of melanocytic nevi (n = 46) and primary melanomas (n = 42). Exome sequencing revealed that dysplastic nevi harbored a substantially lower mutational load than melanomas (21 protein-changing mutations versus >100). Known "driver" mutations in genes for melanoma, including CDKN2A, TP53, NF1, RAC1, and PTEN, were not found among any melanocytic nevi sequenced. Additionally, melanocytic nevi including dysplastic nevi showed a significantly lower frequency and a different UV-associated mutational signature. These results show that although melanocytic nevi and dysplastic nevi harbor stable genomes with relatively few alterations, progression into melanomas requires additional mutational processes affecting key tumor suppressors. This study identifies molecular parameters that could be useful for diagnostic platforms.

Massively parallel sequencing analysis of benign melanocytic naevi

“…To ascertain whether the melanocytic naevi reported here harboured similar repertoires of somatic genetic alterations to those of previously reported naevi, we conducted an exploratory analysis comparing the somatic mutation landscapes and the frequencies of CNAs with those of previously reported sequencing studies. 17,18 Analysis of somatic mutation landscapes ( Figure 3A) revealed similar mutation frequencies for BRAF and NRAS between our melanocytic naevi and the dysplastic naevi reported by Melamed et al 18 : 50% (6/12) and 33% (4/12) versus 60% (9/15) and 27% (4/15), respectively. In contrast, the globular naevi and reticular naevi reported by Stark et al 17 showed BRAF mutation frequencies of 75% (9/12) and 39% (7/18), respectively.…”

“…In comparison with the well‐defined mutational landscape of melanomas, there are limited studies defining the mutational landscape of naevi outside of the primary genetic alterations affecting melanomas. Like melanomas, naevi have been found to harbour recurrent mutations affecting BRAF (~80%) and NRAS (~20%) . Here, we employed targeted massively parallel sequencing to investigate the repertoire of somatic genetic alterations affecting cancer genes in melanocytic naevi, including naevi showing lentiginous growth and/or varying levels of atypia.…”

“…Like melanomas, naevi have been found to harbour recurrent mutations affecting BRAF (~80%) and NRAS (~20%). [14][15][16][17][18] Here, we employed targeted massively parallel sequencing to investigate the repertoire of somatic genetic alterations affecting cancer genes in melanocytic naevi, including naevi showing lentiginous growth and/or varying levels of atypia.…”

Defining the Molecular Genetics of Dermoscopic Naevus Patterns

“…More recently, whole-exome sequencing of 19 naevi comprising 11 “dysplastic” naevi derived from patients with atypical naevus syndrome, 2 CMN and 6 AMN demonstrated a substantially lower mutational load than cutaneous melanoma and a different and lower frequency of UVR-associated mutational signature, together with an absence of known melanoma driver mutations [68]. …”

An update in the management of malignant melanoma

“…Studies showed that reactivation of TERT (Telomerase Reverse Transcriptase) is an important step in the progression of nevi to malignant melanoma [6] . Dysplastic nevi and melanocytic nevi mostly have certain gene modifications, but gene alteration alone is not sufficient for the development of melanoma [7] . Tissue proteins such as RNA-binding protein (RBP) UNR/CSDE1, Neurotrophin Neuritin1 (NRN1), and Toll-like receptors (TLRs) 2-5, 7, 9, 10 are overexpressed in melanoma.…”