Next-Generation sequencing (NGS) of melanomas has unraveled critical “driver” genes and genomic abnormalities, mostly defined as occurring at high frequency. In addition, less abundant mutations are present that link melanoma to a set of disorders, commonly called RASopathies. These disorders which include neurofibromatosis, Noonan and Legius syndromes, harbor germline mutations in various RAS/MAPK signaling pathway genes. We highlight shared amino acid substitutions between this set of RASopathy mutations and those observed in large-scale melanoma sequencing data, uncovering a significant overlap. We review the evidence that these mutations activate the MAPK pathway in melanoma, and are involved in melanomagenesis. Furthermore, we discuss the observations that two or more RASopathy mutations often co-occur in melanoma, and may act synergistically on activating the pathway.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.