title: BRAF fusions define a distinct molecular subset of melanomas with potential sensitivity to MEK inhibition.
abstract: OBJECTIVE
  Recurrent "driver" mutations at specific loci in BRAF, NRAS, KIT, GNAQ, and GNA11 define clinically relevant molecular subsets of melanoma, but more than 30% are "pan-negative" for these recurrent mutations. We sought to identify additional potential drivers in "pan-negative" melanoma.
  
  
  METHODS
  Using a targeted next-generation sequencing (NGS) assay (FoundationOne™) and targeted RNA sequencing, we identified a novel PAPSS1-BRAF fusion in a "pan-negative" melanoma. We then analyzed NGS data from 51 additional melanomas genotyped by FoundationOne™, as well as melanoma RNA, whole-genome and whole-exome sequencing data in The Cancer Genome Atlas (TCGA), to determine the potential frequency of BRAF fusions in melanoma. We characterized the signaling properties of confirmed molecular alterations by ectopic expression of engineered cDNAs in 293H cells.
  
  
  RESULTS
  Activation of the mitogen-activated protein kinase (MAPK) pathway in cells by ectopic expression of PAPSS1-BRAF was abrogated by mitogen-activated protein kinase kinase (MEK) inhibition but not by BRAF inhibition. NGS data analysis of 51 additional melanomas revealed a second BRAF fusion (TRIM24-BRAF) in a "pan-negative" sample; MAPK signaling induced by TRIM24-BRAF was also MEK inhibitor sensitive. Through mining TCGA skin cutaneous melanoma dataset, we further identified two potential BRAF fusions in another 49 "pan-negative" cases.
  
  
  CONCLUSIONS
  BRAF fusions define a new molecular subset of melanoma, potentially comprising 4% to 8% of "pan-negative" cases. Their presence may explain an unexpected clinical response to MEK inhibitor therapy or assist in selecting patients for MEK-directed therapy.
authors.affiliation: Authors' Affiliations: Departments of Cancer Biology, Biochemistry, Vanderbilt-Ingram Cancer Center; Departments of Pathology, Microbiology, and Immunology, Medicine, Division of Hematology-Oncology, Vanderbilt University School of Medicine; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee; Foundation Medicine, Inc., Cambridge, Massachusetts; and Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Hutchinson
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.forename: Geoff
authors.initials: G
authors.lastname: Otto
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lehmann
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Lyle
authors.forename: Cindy L
authors.initials: CL
authors.lastname: Vnencak-Jones
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Pietenpol
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: William
authors.initials: W
authors.lastname: Pao
mesh_terms: D000328:Adult; D045744:Cell Line, Tumor; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D008545:Melanoma / Q000145:classification / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009097:Multienzyme Complexes / Q000235:genetics; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D013430:Sulfate Adenylyltransferase / Q000235:genetics
chemical_list: D009097:Multienzyme Complexes; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; C022322:PAPS synthetase; D013430:Sulfate Adenylyltransferase