GNA11 and N‐RAS mutations: alternatives for MAPK pathway activating GNAQ mutations in primary melanocytic tumours of the central nervous system

Abstract

In primary melanocytic tumours of the CNS, GNA11 and N-RAS mutations represent a mechanism of MAPK pathway activation alternative to the common GNAQ mutations. On the other hand, BRAF(V600E) mutations and activating KIT mutations seem to be absent or very rare in these tumours.

Primary Melanocytic Tumors of the Central Nervous System: a Review with Focus on Molecular Aspects

“…(Table 3) Of note, the number of esp. primary leptomeningeal melanoma cases analyzed is limited (45,71,77,139). A BRAF V600E mutation has recently been reported in an unusual case of leptomeningeal melanocytoma in assocation with a congenital nevus of Ota in a 15-year-old boy.…”

“…Oncogenic mutations in these genes are found in benign as well as malignant LMNs and have up to now only been reported in adult patients with circumscribed tumors, except for a 15-year-old boy with a GNA11-mutated melanocytoma in the series of Koelsche et al (28,44,45,71,75,77,96,126). Like in uveal melanomas, activating mutations in GNAQ and GNA11 in LMNs mainly affect codon 209 and consist of substitution of glutamine to leucine [c.626 A>T (p.(Gln209Leu))] or, less frequently, by substitution to proline [c.626 A>C (p.(Gln209Pro))] (45,71,75,77). Only a single case of spinal melanocytoma with a codon 183 GNAQ mutation {c.548 G>A [p.(Arg183Gln)]} has been described (96).…”

“…This concerned a tumor in the spinal region in a 40-year-old woman. Whether this patient had a congenital background of her disease is unknown (45). Importantly, in primary LMNs in children NRAS mutations occur more frequently (see later).…”

Melanoma Epidemiology and Prevention

“…Less frequently, melanomas contain KIT mutations, particularly mucosal melanoma or melanomas arising on acral or on sun-damaged sites [53]. GNAQ and GNA11 mutations were discovered in uveal and CNS melanomas, defining additional molecular melanoma subgroups [81,129,200]. Frequently, melanomas also contain PTEN, CDKN2A, CDK4, and CCND1 copy number alterations that help to define molecular subgroups [54,55].…”

Nras in melanoma: Targeting the undruggable target

“…Recently, different studies have demonstrated that early embryonic/post zygotic somatic mutations in the NRAS gene are implicated in the development of neurocutaneous melanocytosis, a rare congenital disorder, in which affected patients have an increased number of melanocytes in the leptomeninges and the skin, with a large congenital melanocytic nevus usually associated with so-called "satellites" in the vicinity, and childhood melanoma of the central nervous system [46][47][48]. In line with these observations, recently it has been shown that primary melanoma of the CNS in children carries oncogenic mutations in NRAS, unlike primary melanoma of the central nervous system in adults, in which NRAS is not a common driver oncogene [46].…”