title: Characterization of FN1-FGFR1 and novel FN1-FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors.
abstract: Phosphaturic mesenchymal tumors typically cause paraneoplastic osteomalacia, chiefly as a result of FGF23 secretion. In a prior study, we identified FN1-FGFR1 fusion in 9 of 15 phosphaturic mesenchymal tumors. In this study, a total of 66 phosphaturic mesenchymal tumors and 7 tumors resembling phosphaturic mesenchymal tumor but without known phosphaturia were studied. A novel FN1-FGF1 fusion gene was identified in two cases without FN1-FGFR1 fusion by RNA sequencing and cross-validated with direct sequencing and western blot. Fluorescence in situ hybridization analyses revealed FN1-FGFR1 fusion in 16 of 39 (41%) phosphaturic mesenchymal tumors and identified an additional case with FN1-FGF1 fusion. The two fusion genes were mutually exclusive. Combined with previous data, the overall prevalence of FN1-FGFR1 and FN1-FGF1 fusions was 42% (21/50) and 6% (3/50), respectively. FGFR1 immunohistochemistry was positive in 82% (45/55) of phosphaturic mesenchymal tumors regardless of fusion status. By contrast, 121 cases of potential morphologic mimics (belonging to 13 tumor types) rarely expressed FGFR1, the main exceptions being solitary fibrous tumors (positive in 40%), chondroblastomas (40%), and giant cell tumors of bone (38%), suggesting a possible role for FGFR1 immunohistochemistry in the diagnosis of phosphaturic mesenchymal tumor. With the exception of one case reported in our prior study, none of the remaining tumors resembling phosphaturic mesenchymal tumor had either fusion type or expressed significant FGFR1. Our findings provide insight into possible mechanisms underlying the pathogenesis of phosphaturic mesenchymal tumor and imply a central role of the FGF1-FGFR1 signaling pathway. The novel FN1-FGF1 protein is expected to be secreted and serves as a ligand that binds and activates FGFR1 to achieve an autocrine loop. Further study is required to determine the functions of these fusion proteins.
authors.affiliation: Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Jen-Chieh
authors.identifier: 0000-0001-7739-5934
authors.initials: JC
authors.lastname: Lee
authors.affiliation: Institute of Information Science, Academia Sinica, Taipei, Taiwan.|Bioinformatics Program, Taiwan International Graduate Program, Academia Sinica, Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Sheng-Yao
authors.initials: SY
authors.lastname: Su
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.|Integrated Laboratory, Center of Translational Medicine, Graduate Institute of Translational Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chun A
authors.initials: CA
authors.lastname: Changou
authors.affiliation: Department of Orthopedics, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Rong-Sen
authors.initials: RS
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Keh-Sung
authors.initials: KS
authors.lastname: Tsai
authors.affiliation: Skeletal Clinical Studies Unit, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Collins
authors.affiliation: Bone and Mineral Unit, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Orwoll
authors.affiliation: Institute of Information Science, Academia Sinica, Taipei, Taiwan.
authors.forename: Chung-Yen
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Institute of Information Science, Academia Sinica, Taipei, Taiwan.
authors.forename: Shu-Hwa
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Shyang-Rong
authors.initials: SR
authors.lastname: Shih
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta and Royal Alexandra Hospital, Edmonton, Alberta, Canada.
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
authors.affiliation: Department of Pathology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Billings
authors.affiliation: Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: G Petur
authors.initials: GP
authors.lastname: Nielsen
authors.affiliation: Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Konishi
authors.affiliation: Department of Pathology, National University Health System, Singapore, Singapore.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Petersson
authors.affiliation: Department of Pediatrics (Endocrinology), Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Carpenter
authors.affiliation: Pathology Department, Singapore General Hospital, Singapore, Singapore.
authors.forename: Kesavan
authors.initials: K
authors.lastname: Sittampalam
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Hsuan-Ying
authors.initials: HY
authors.lastname: Huang
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Folpe
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics*; D016220:Fibroblast Growth Factor 1 / Q000235:genetics*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics*; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D012983:Soft Tissue Neoplasms / Q000235:genetics*
chemical_list: C000717427:FGF23 protein, human; C067625:FN1 protein, human; D005353:Fibronectins; D015514:Oncogene Proteins, Fusion; D016220:Fibroblast Growth Factor 1; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1