title: Fusion events lead to truncation of FOS in epithelioid hemangioma of bone.
abstract: Epithelioid hemangioma of bone is a locally aggressive vascular neoplasm. It can be challenging to diagnose because of the wide histological spectrum, which can make it difficult to differentiate from other vascular neoplasms such as epithelioid hemangioendothelioma or epithelioid angiosarcoma. COBRA-FISH karyotyping identified a balanced t(3;14) translocation. Transcriptome sequencing of the index case and two other epithelioid hemangiomas revealed a recurrent translocation breakpoint involving the FOS gene, which was fused to different partners in all three cases. The break was observed in exon 4 of the FOS gene and the fusion event led to the introduction of a stop codon. In all instances, the truncation of the FOS gene would result in the loss of the transactivation domain (TAD). Using FISH probes we found a break in the FOS gene in two additional cases, in none of these cases a recurrent fusion partner could be identified. In total, FOS was split in 5/7 evaluable samples. We did not observe point mutations leading to early stop codons in any of the 10 cases where RNA was available. Detection of FOS rearrangement may be a useful diagnostic tool to assist in the often difficult differential diagnosis of vascular tumors of bone. Our data suggest that the translocation causes truncation of the FOS protein, with loss of the TAD, which is thereby a novel mechanism involved in tumorigenesis.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: David G P
authors.initials: DG
authors.lastname: van IJzendoorn
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Danielle
authors.initials: D
authors.lastname: de Jong
authors.affiliation: Department of Pathology, Hospital Vall D'hebron, Barcelona, Spain.
authors.forename: Cleofe
authors.initials: C
authors.lastname: Romagosa
authors.affiliation: Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.affiliation: Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy.
authors.forename: Maria Serena
authors.initials: MS
authors.lastname: Benassi
authors.affiliation: Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gambarotti
authors.affiliation: Department of Pathology, University of Copenhagen, Denmark.
authors.forename: Soeren
authors.initials: S
authors.lastname: Daugaard
authors.affiliation: Department of Orthopedic Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: van de Sande
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Karoly
authors.initials: K
authors.lastname: Szuhai
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Judith V M G
authors.initials: JV
authors.lastname: Bovée
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D005091:Exons; D005260:Female; D050939:Gene Fusion; D006391:Hemangioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007621:Karyotyping; D008297:Male; D008875:Middle Aged; D016761:Oncogene Proteins v-fos / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics; D059467:Transcriptome; D014178:Translocation, Genetic
chemical_list: C493663:MBNL1 protein, human; D016761:Oncogene Proteins v-fos; D016601:RNA-Binding Proteins