Activating mutations of the GNAQ gene: a frequent event in primary melanocytic neoplasms of the central nervous system

Abstract

Primary melanocytic neoplasms of the central nervous system (CNS) are uncommon neoplasms derived from melanocytes that normally can be found in the leptomeninges. They cover a spectrum of malignancy grades ranging from low-grade melanocytomas to lesions of intermediate malignancy and overtly malignant melanomas. Characteristic genetic alterations in this group of neoplasms have not yet been identified. Using direct sequencing, we investigated 19 primary melanocytic lesions of the CNS (12 melanocytomas, 3 intermediate-grade melanocytomas, and 4 melanomas) for hotspot oncogenic mutations commonly found in melanocytic tumors of the skin (BRAF, NRAS, and HRAS genes) and uvea (GNAQ gene). Somatic mutations in the GNAQ gene at codon 209, resulting in constitutive activation of GNAQ, were detected in 7/19 (37%) tumors, including 6/12 melanocytomas, 0/3 intermediate-grade melanocytomas, and 1/4 melanomas. These GNAQ-mutated tumors were predominantly located around the spinal cord (6/7). One melanoma carried a BRAF point mutation that is frequently found in cutaneous melanomas (c.1799 T>A, p.V600E), raising the question whether this is a metastatic rather than a primary tumor. No HRAS or NRAS mutations were detected. We conclude that somatic mutations in the GNAQ gene at codon 209 are a frequent event in primary melanocytic neoplasms of the CNS. This finding provides new insight in the pathogenesis of these lesions and suggests that GNAQ-dependent mitogen-activated kinase signaling is a promising therapeutic target in these tumors. The prognostic and predictive value of GNAQ mutations in primary melanocytic lesions of the CNS needs to be determined in future studies.

Fig. 1

Heavily pigmented melanocytoma adjacent to the thoracic spinal cord (patient 12) consisting of spindle cells arranged in fascicles (a) (magnification 400×). Epithelioid cell morphology in an intermediate-grade melanocytoma (patient 17) showing increased mitotic activity (2/10 HPFs) (b) (arrow) (magnification 200×). Intermediate-grade melanocytoma showing invasion in the thoracic spinal cord (c) (patient 1); note the Rosenthal fiber (arrow) in the surrounding neuropil (magnification 200×). Strong nuclear pleomorphism and high mitotic activity (arrows) in a melanoma in the sacral region (d) (patient 10) (magnification 200×)

Fig. 2

Sequence tracings for GNAQ surrounding codon 209. Wild type (CAA) (a), CAA > CTA (b), and CAA > CCA (c). *‘W’ is the nucleotide code for A/T according to the Kyoto Encyclopedia of Genes and Genomes (http://www.genome.jp/kegg/catalog/codes1.html)