Department of Pathology C66, Canisius Wilhelmina Hospital, and Department of Pathology, Radboud University Nijmegen Medical Centre, P.O. Box 9015, 6500 GS Nijmegen, The Netherlands.
Acta Neuropathol. 2010 Mar;119(3):317-23. doi: 10.1007/s00401-009-0611-3.
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.
中枢神经系统（CNS）的原发性黑色素细胞肿瘤是源自黑色素细胞的罕见肿瘤，这些黑色素细胞通常存在于软脑膜中。它们涵盖了从低级别黑色素细胞瘤到中级恶性和明显恶性黑色素瘤的一系列恶性程度等级。该组肿瘤的特征性遗传改变尚未确定。使用直接测序，我们研究了 19 例中枢神经系统原发性黑色素细胞病变（12 例黑色素细胞瘤、3 例中级黑色素细胞瘤和 4 例黑色素瘤），以检测常见于皮肤黑色素瘤（BRAF、NRAS 和 HRAS 基因）和葡萄膜黑色素瘤（GNAQ 基因）的热点致癌突变。在 19 个肿瘤中有 7 个（37%）检测到 GNAQ 基因 209 密码子的体细胞突变，导致 GNAQ 持续激活，包括 6 个黑色素细胞瘤、0 个中级黑色素细胞瘤和 1 个黑色素瘤。这些 GNAQ 突变肿瘤主要位于脊髓周围（6/7）。1 个黑色素瘤携带了一种经常在皮肤黑色素瘤中发现的 BRAF 点突变（c.1799 T>A，p.V600E），这提出了一个问题，即这是否是一个转移性肿瘤而不是原发性肿瘤。未检测到 HRAS 或 NRAS 突变。我们得出结论，GNAQ 基因 209 密码子的体细胞突变是中枢神经系统原发性黑色素细胞肿瘤的常见事件。这一发现为这些病变的发病机制提供了新的见解，并表明 GNAQ 依赖性丝裂原活化蛋白激酶信号传导是这些肿瘤有前途的治疗靶点。在未来的研究中，需要确定 CNS 原发性黑色素细胞病变中 GNAQ 突变的预后和预测价值。
