Molecular genomic profiling of melanocytic nevi.

Abstract

The benign melanocytic nevus is the commonest tumor in humans and rarely transforms into cutaneous melanoma. Elucidation of the nevus genome is required to better understand the molecular steps of progression to melanoma. We performed whole genome sequencing on a series of 14 benign melanocytic nevi, consisting of both congenital and acquired types. All nevi had driver mutations in the MAPK signalling pathway, either BRAF V600E or NRAS Q61R/L. No additional definite driver mutations were identified. Somatic mutations in nevi with higher mutation loads showed a predominance of mutational signatures 7a and 7b, consistent with ultraviolet radiation exposure, whereas nevi with lower mutation loads (including all three congenital nevi) had a predominance of the ubiquitous signatures 1 and 5. Two nevi had mutations in promoter regions predicted to bind ETS-family transcription factors as well as subclonal mutations in the TERT promoter. This paper presents whole genome data from melanocytic nevi. We confirm that ultraviolet radiation is involved in the etiology of a subset of nevi. This study also establishes that TERT promoter mutations are present in morphologically benign skin nevi in subclonal populations, which has implications regarding the interpretation of this emerging biomarker in sensitive assays.