Artikel
MAPK pathway activation by GNAQ and GNA11 mutations in melanocytic tumors of the central nervous system.
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Veröffentlicht: | 11. September 2012 |
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Gliederung
Text
Activation of the mitogen-activated protein kinase (MAPK) pathway, leading to over-expression of p-ERK is considered to be pivotal for melanocytes proliferation and considered an early event in melanoma development. In melanocytic tumor of the CNS, such event seems however not to depend on activating BRAF or N-RAS mutations, as observed in cutaneous melanocytic nevi as well as melanomas. The MAPK activation may, however, be dependent on alterations of other genes such as GNAQ, GNA11 and KIT, which have been found frequently mutated in uveal melanomas, the melanoma subtype which shows some histological and molecular similarities to melanocytic tumors of the CNS. In this study, we investigated the mutational status of GNAQ, GNA11, KIT, BRAF, N-RAS and H-RAS in a series of 21 melanocytic tumors of the CNS with a combined pyrosequencing-based, SSCP-based and High Melting Resolution Analysis (HRM)-based approach. The series included 7 melanocytomas, 10 melanocytomas of intermediate differentiation and 4 primary CNS melanomas. We identified six cases harbouring mutations in the hotspot codon 209 of the GNAQ gene and two cases with mutations in the hotspot codon 209 of the GNA11 gene. Two mutations in codon 61 of N-RAS were also detected in the HRM analysis. All identified mutations were mutually exclusive. In the SSCP analysis, no shifts corresponding to BRAFV600E mutations or suggesting mutations in exons 9, 11, 13, 17 of the KIT gene were observed. In conclusion, GNA11 mutations represent an alternative mechanism of MAPK pathway activation in melanocytic tumors of the CNS. Our data confirm also the presence of frequent activating mutations of GNAQ and the occurrence of sporadic N-RAS mutations in such tumors. On the other hand, mutations affecting BRAF and KIT, in contrast to cutaneous melanomas, are absent or very rare in primary melanocytic tumors of the CNS.