title: Recurrent BRAF kinase fusions in melanocytic tumors offer an opportunity for targeted therapy.
abstract: BRAF is the most prevalent oncogene and an important therapeutic target in melanoma. In some cancers, BRAF is activated by rearrangements that fuse its kinase domain to 5' partner genes. We examined 848 comparative genomic hybridization profiles of melanocytic tumors and found copy number transitions within BRAF in 10 tumors, of which six could be further characterized by sequencing. In all, the BRAF kinase domain was fused in-frame to six N-terminal partners. No other mutations were identified in melanoma oncogenes. One of the seven melanoma cell lines without known oncogenic mutations harbored a similar BRAF fusion, which constitutively activated the MAP kinase pathway. Sorafenib, but not vemurafenib, could block MAP kinase pathway activation and proliferation of the cell line at clinically relevant concentrations, whereas BRAF(V) (600E) mutant melanoma cell lines were significantly more sensitive to vemurafenib. The patient from whom the cell line was derived showed a durable clinical response to sorafenib.
authors.affiliation: Departments of Dermatology and Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Botton
authors.forename: Iwei
authors.initials: I
authors.lastname: Yeh
authors.forename: Tyrrell
authors.initials: T
authors.lastname: Nelson
authors.forename: Swapna S
authors.initials: SS
authors.lastname: Vemula
authors.forename: Alyssa
authors.initials: A
authors.lastname: Sparatta
authors.forename: Maria C
authors.initials: MC
authors.lastname: Garrido
authors.forename: Maryline
authors.initials: M
authors.lastname: Allegra
authors.forename: Stephane
authors.initials: S
authors.lastname: Rocchi
authors.forename: Philippe
authors.initials: P
authors.lastname: Bahadoran
authors.forename: Timothy H
authors.initials: TH
authors.lastname: McCalmont
authors.forename: Philip E
authors.initials: PE
authors.lastname: LeBoit
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Burton
authors.forename: Gideon
authors.initials: G
authors.lastname: Bollag
authors.forename: Robert
authors.initials: R
authors.lastname: Ballotti
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
mesh_terms: D000293:Adolescent; D000328:Adult; D002675:Child, Preschool; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015321:Gene Rearrangement / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008544:Melanocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D018332:Nevus, Epithelioid and Spindle Cell / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D000077157:Sorafenib; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D000077484:Vemurafenib; D055815:Young Adult
chemical_list: D007211:Indoles; D015514:Oncogene Proteins, Fusion; D010671:Phenylurea Compounds; D013449:Sulfonamides; D000077484:Vemurafenib; D009536:Niacinamide; D000077157:Sorafenib; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; kinase; melanoma; oncogenes; translocation
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