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Review
. 2016 Sep;136(9):1755-1759.
doi: 10.1016/j.jid.2016.05.095. Epub 2016 May 25.

RASopathy Gene Mutations in Melanoma

Affiliations
Review

RASopathy Gene Mutations in Melanoma

Ruth Halaban et al. J Invest Dermatol. 2016 Sep.

Abstract

Next-generation sequencing 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 and Noonan and Legius syndromes, harbor germline mutations in various RAS/mitogen-activated protein kinase 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 RAS/mitogen-activated protein kinase 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.

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Conflict of interest statement

The authors state no conflict of interest.

Figures

Figure 1
Figure 1
MAPK kinase pathway indicating RASopathy mutant genes and those shared with melanoma. The green and yellow are RASopathy genes with (presumably) activating and inactivating mutations, respectively. Those with amino acid changes shared with melanoma are marked with a red dot. RTK, Receptor Tyrosine Kinase. CFCS: Cardio-facio-cutaneous syndrome. Noonan-LS, Noonan-like syndrome. Please see the text for more details.
Figure 2
Figure 2
Schematic representation of RASA2 and PTPN11 mutations in melanomas and RASopathies. The mutations indicated above and below the bar are those identified in melanoma and those shared with RASopathy syndromes, respectively. In blue are mutations shared with other cancers. NS, Noonan syndrome; LS, Legius Syndrome; LP, LEOPARD syndrome. The bars indicate conserved domains. a. RASA2: C2, Protein kinase C conserved region 2; RAS-GAP, GTPase-activator protein for Ras-like GTPases; PH: Pleckstrin homology-like domain; BTK, Bruton’s tyrosine kinase Cys-rich motif. b. PTPN11: SH2: Src homology 2 domain; SB, Substrate binding site. Numbers below the bars indicate the AA positions.

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