title: Aneurysmal bone cyst variant translocations upregulate USP6 transcription by promoter swapping with the ZNF9, COL1A1, TRAP150, and OMD genes.
abstract: Aneurysmal bone cysts (ABC) are locally aggressive bone tumors that often feature chromosome 17p13 rearrangements. One of the ABC 17p13 rearrangements--t(16;17)(q22;p13)--was recently shown to create a CDH11-USP6 fusion in which the USP6/TRE17 oncogene is overexpressed through juxtaposition with the CDH11 promoter. Herein, we characterize four different ABC translocations involving 17p13, and we show that each is associated with a novel USP6 fusion oncogene. Specifically, we demonstrate that t(1;17), t(3;17), t(9;17), and t(17;17) result in USP6 fusions with TRAP150 (thyroid receptor-associated protein 150), ZNF9 (ZiNc Finger 9), Osteomodulin, and COL1A1 (Collagen 1A1), respectively. The oncogenic mechanism in these fusion genes is akin to CDH11-USP6, with the USP6 coding sequences juxtaposed to the promoter regions in each of the four novel translocation partners. The novel fusion partners appear well suited to drive USP6 transcription in the bone/mesenchymal context: osteomodulin is expressed strongly in osteoblastic lineages, and the COL1A1 promoter has an oncogenic role in the mesenchymal cancer dermatofibrosarcoma protuberans. In summary, these studies show that USP6 oncogenic activation results from heterogeneous genomic mechanisms involving USP6 transcriptional upregulation by juxtaposition with ectopic promoters.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. oliveira.andre@mayo.edu
authors.forename: Andre M
authors.initials: AM
authors.lastname: Oliveira
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Perez-Atayde
authors.forename: Paola
authors.initials: P
authors.lastname: Dal Cin
authors.forename: Mark C
authors.initials: MC
authors.lastname: Gebhardt
authors.forename: Chang-Jie
authors.initials: CJ
authors.lastname: Chen
authors.forename: James R
authors.initials: JR
authors.lastname: Neff
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Rosenberg
authors.forename: Julia A
authors.initials: JA
authors.lastname: Bridge
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
mesh_terms: D017824:Bone Cysts, Aneurysmal / Q000235:genetics* / Q000473:pathology; D002648:Child; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D008297:Male; D009857:Oncogenes; D011401:Promoter Regions, Genetic / Q000235:genetics; D011509:Proteoglycans / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D015854:Up-Regulation
chemical_list: C433227:CNBP protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D004268:DNA-Binding Proteins; D011509:Proteoglycans; D016601:RNA-Binding Proteins; C475774:THRAP3 protein, human; D014157:Transcription Factors