title: Targeted next generation sequencing reveals unique mutation profile of primary melanocytic tumors of the central nervous system.
abstract: Melanocytic tumors originating in the central nervous system (MT-CNS) are rare tumors that generally have a favorable prognosis, however malignant tumors do occur. Pathogenetically MT-CNS are not well characterized. Similar to uveal melanoma and blue nevi, they frequently harbor activating GNAQ or GNA11 mutations. Rare NRAS mutations have also been reported. Other mutations have not yet been described. We analyzed 19 MT-CNS, 7 uveal melanomas and 19 cutaneous melanomas using a targeted next generation sequencing approach analyzing 29 genes known to be frequently mutated in other melanocytic tumors (in particular uveal and cutaneous melanomas). In concordance with previous studies, cutaneous melanoma samples showed frequent NRAS or BRAF mutations, as well as mutations in other genes (e.g. NF1, RAC1, PIK3CA, ARID1A). Metastasized uveal melanomas exhibited mutations in GNAQ, GNA11 and BAP1. In contrast, MT-CNS almost exclusively demonstrated mutations in GNAQ (71 %) or GNA11 (12 %). Interestingly both GNA11 mutations identified were detected in MT-CNS diagnosed as intermediate grade melanocytomas which also recurred. One of these recurrent cases also harbored an inactivating BAP1 mutation and was found to have lost one copy of chromosome 3. Our findings show that while MT-CNS do have GNAQ or GNA11 mutations, they rarely harbor other recurrent mutations found in uveal or cutaneous melanomas. Considering chromosome 3 and BAP1 loss are robust markers of poor prognosis in uveal melanoma, it will prove interesting to determine whether these genomic alterations are also of prognostic significance in MT-CNS.
authors.affiliation: Institute of Neuropathology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Duisburg-Essen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: van de Nes
authors.affiliation: Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Gessi
authors.affiliation: Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK) University of Duisburg-Essen, Duisburg-Essen, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Sucker
authors.affiliation: Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK) University of Duisburg-Essen, Duisburg-Essen, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Möller
authors.affiliation: Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK) University of Duisburg-Essen, Duisburg-Essen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Stiller
authors.affiliation: Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK) University of Duisburg-Essen, Duisburg-Essen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Horn
authors.affiliation: Department of Ophthalmology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Duisburg-Essen, Germany.
authors.forename: Simone L
authors.initials: SL
authors.lastname: Scholz
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Carina
authors.initials: C
authors.lastname: Pischler
authors.affiliation: Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK) University of Duisburg-Essen, Duisburg-Essen, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Stadtler
authors.affiliation: Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK) University of Duisburg-Essen, Duisburg-Essen, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Schilling
authors.affiliation: Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK) University of Duisburg-Essen, Duisburg-Essen, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zimmer
authors.affiliation: Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK) University of Duisburg-Essen, Duisburg-Essen, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Hillen
authors.affiliation: Tissue Pathology and Diagnostic Oncology, Camperdown, NSW, Australia.|The University of Sydney, Camperdown, NSW, Australia.|Melanoma Institute Australia, North Sydney, NSW, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: Department of Neuropathology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.|The University of Sydney, Camperdown, NSW, Australia.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Buckland
authors.affiliation: Department of Pathology, Catholic University, Rome, Italy.
authors.forename: Libero
authors.initials: L
authors.lastname: Lauriola
authors.affiliation: Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.affiliation: Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Waha
authors.affiliation: Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK) University of Duisburg-Essen, Duisburg-Essen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Rajmohan
authors.initials: R
authors.lastname: Murali
authors.affiliation: Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK) University of Duisburg-Essen, Duisburg-Essen, Germany. klaus.griewank@uk-essen.de.
authors.forename: Klaus G
authors.initials: KG
authors.lastname: Griewank
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations; D005260:Female; D005500:Follow-Up Studies; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008577:Meningeal Neoplasms / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics; D055815:Young Adult
chemical_list: C400134:BAP1 protein, human; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase
keywords: BAP1; GNA11; GNAQ; Melanocytoma