title: Mutations in g protein encoding genes and chromosomal alterations in primary leptomeningeal melanocytic neoplasms.
abstract: Limited data is available on the genetic features of primary leptomeningeal melanocytic neoplasms (LMNs). Similarities with uveal melanoma were recently suggested as both entities harbor oncogenic mutations in GNAQ and GNA11. Whether primary LMNs share additional genetic alterations with uveal melanoma including copy number variations is unknown. Twenty primary LMNs ranging from benign and intermediate-grade melanocytomas to melanomas were tested by direct sequencing for hotspot mutations in the genes GNA11, GNAQ, BRAF, NRAS and HRAS. Furthermore, the lesions were tested for copy number variations of chromosomes frequently present in uveal melanoma (1p, 3, 6 and 8q) by multiplex ligation-dependent probe amplification (MLPA). Genome-wide analyses of copy number alterations of two leptomeningeal melanocytic neoplasms were performed using the OncoScan SNP-array. GNAQ(Q209) mutations were present in eleven LMNs, while two of 20 cases carried a GNA11(Q209) mutation. No BRAF, HRAS or NRAS hotspot mutations were detected. Monosomy 3 and gain of 8q were present in one leptomeningeal melanoma, and one intermediate-grade melanocytoma harbored a gain of chromosome 6. With MLPA, the melanocytomas did not show any further gross chromosomal variations. Our data shows that primary LMNs, like uveal melanoma, harbor oncogenic mutations in GNAQ and GNA11 but lack mutations in BRAF, NRAS and HRAS. This finding may help in the differential diagnosis between a primary LMN and a metastasis from a cutaneous melanoma to the central nervous system. Copy number variations in some aggressive LMNs resemble those present in uveal melanoma but their prognostic significance is unclear.
authors.affiliation: Department of Pathology, C66, Canisius Wilhelmina Hospital, P.O. Box 9015, 6500 GS, Nijmegen, The Netherlands, h.kusters@cwz.nl.
authors.forename: Heidi V N
authors.initials: HV
authors.lastname: Küsters-Vandevelde
authors.forename: Ilse A C H
authors.initials: IA
authors.lastname: van Engen-van Grunsven
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Coupland
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Lake
authors.forename: Jos
authors.initials: J
authors.lastname: Rijntjes
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.forename: Benno
authors.initials: B
authors.lastname: Küsters
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
authors.forename: Willeke A M
authors.initials: WA
authors.lastname: Blokx
authors.forename: Patricia J T A
authors.initials: PJ
authors.lastname: Groenen
mesh_terms: D000328:Adult; D000368:Aged; D002869:Chromosome Aberrations; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019204:GTP-Binding Proteins / Q000235:genetics*; D052138:Genes, Neoplasm / Q000235:genetics*; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000473:pathology; D008545:Melanoma / Q000235:genetics / Q000473:pathology; D008577:Meningeal Neoplasms / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: C554062:GNA11 protein, human; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; D019204:GTP-Binding Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11