title: Activating cysteinyl leukotriene receptor 2 (CYSLTR2) mutations in blue nevi.
abstract: Blue nevi are common melanocytic tumors arising in the dermal layer of the skin. Similar to uveal melanomas, blue nevi frequently harbor GNAQ and GNA11 mutations. Recently, recurrent CYSLTR2 and PLCB4 mutations were identified in uveal melanomas not harboring GNAQ or GNA11 mutations. All four genes (GNAQ, GNA11, CYSLTR2, and PLCB4) code for proteins involved in the same signaling pathway, which is activated by mutations in these genes. Given the related functional consequences of these mutations and the known genetic similarities between uveal melanoma and blue nevi, we analyzed a cohort of blue nevi to investigate whether CYSLTR2 and PLCB4 mutations occur in tumors lacking GNAQ or GNA11 mutations (as in uveal melanoma). A targeted next-generation sequencing assay covering known activating mutations in GNAQ, GNA11, CYSLTR2, PLCB4, KIT, NRAS, and BRAF was applied to 103 blue nevi. As previously reported, most blue nevi were found to harbor activating mutations in GNAQ (59%, n=61), followed by less frequent mutations in GNA11 (16%, n=17). Additionally, one BRAF (1%) and three NRAS (3%) mutations were detected. In three tumors (3%) harboring none of the aforementioned gene alterations, CYSLTR2 mutations were identified. All three CYSLTR2 mutations were the same c.386T>A, L129Q mutation previously identified in uveal melanoma that has been shown to lead to increased receptor activation and signaling. In summary, our study identifies CYSLTR2 L129Q alterations as a previously unrecognized activating mutation in blue nevi, occuring in a mutually exclusive fashion with known GNAQ and GNA11 mutations. Similar to GNAQ and GNA11 mutations, CYSLTR2 mutations, when present, are likely defining pathogenetic events in blue nevi.
authors.affiliation: Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Möller
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Rajmohan
authors.initials: R
authors.lastname: Murali
authors.affiliation: Dermatopathology Friedrichshafen, Friedrichshafen, Germany.
authors.forename: Hansgeorg
authors.initials: H
authors.lastname: Müller
authors.affiliation: Department of Dermatology, Medical University of Graz, Graz, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wiesner
authors.affiliation: Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.|Discipline of Pathology, Sydney Medical School, The University of Sydney, Camperdown,NSW, Australia.|Melanoma Institute Australia, North Sydney, NSW, Australia.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Jackett
authors.affiliation: Department of Ophthalmology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.
authors.forename: Simone L
authors.initials: SL
authors.lastname: Scholz
authors.affiliation: Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.
authors.forename: Ioana
authors.initials: I
authors.lastname: Cosgarea
authors.affiliation: Institute of Neuropathology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.
authors.forename: Johannes Ap
authors.initials: JA
authors.lastname: van de Nes
authors.affiliation: Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), 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), Essen, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Hillen
authors.affiliation: Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), 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), Essen, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Paschen
authors.affiliation: Dermatopathology Friedrichshafen, Friedrichshafen, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Kutzner
authors.affiliation: Dermatopathology Friedrichshafen, Friedrichshafen, Germany.
authors.forename: Arno
authors.initials: A
authors.lastname: Rütten
authors.affiliation: Dermatopathologie bei Mainz, Nieder-Olm, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Böckers
authors.affiliation: Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.|Discipline of Pathology, Sydney Medical School, 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 Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.|Dermatopathologie bei Mainz, Nieder-Olm, Germany.
authors.forename: Klaus G
authors.initials: KG
authors.lastname: Griewank
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018329:Nevus, Blue / Q000235:genetics* / Q000473:pathology; D054799:Phospholipase C beta / Q000235:genetics; D018077:Receptors, Leukotriene / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: C554062:GNA11 protein, human; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; D018077:Receptors, Leukotriene; C412375:cysteinyl leukotriene receptor 2; C518042:PLCB4 protein, human; D054799:Phospholipase C beta; D043802:GTP-Binding Protein alpha Subunits, Gq-G11