Characterization of FN1–FGFR1 and novel FN1–FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors

Jen Chieh Lee, Sheng Yao Su, Chun A. Changou, Rong Sen Yang, Keh Sung Tsai, Michael T. Collins, Eric Orwoll, Chung Yen Lin, Shu Hwa Chen, Shyang Rong Shih, Cheng Han Lee, Yoshinao Oda, Steven D. Billings, Chien Feng Li, G. Petur Nielsen, Eiichi Konishi, Fredrik Petersson, Thomas O. Carpenter, Kesavan Sittampalam, Hsuan Ying Huang & 1 others Andrew L. Folpe

Research output: Contribution to journalArticle

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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.Modern Pathology advance online publication, 22 July 2016; doi:10.1038/modpathol.2016.137.

Original languageEnglish (US)
JournalModern Pathology
DOIs
StateAccepted/In press - Jul 22 2016

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Gene Fusion
Neoplasms
Chondroblastoma
Immunohistochemistry
Familial Hypophosphatemia
Solitary Fibrous Tumors
Giant Cell Tumor of Bone
RNA Sequence Analysis
Fibroblast Growth Factor 1
Osteomalacia
Fluorescence In Situ Hybridization
Publications
Proteins
Western Blotting
Pathology
Ligands

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Lee, J. C., Su, S. Y., Changou, C. A., Yang, R. S., Tsai, K. S., Collins, M. T., ... Folpe, A. L. (Accepted/In press). Characterization of FN1–FGFR1 and novel FN1–FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors. Modern Pathology. https://doi.org/10.1038/modpathol.2016.137

Characterization of FN1–FGFR1 and novel FN1–FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors. / Lee, Jen Chieh; Su, Sheng Yao; Changou, Chun A.; Yang, Rong Sen; Tsai, Keh Sung; Collins, Michael T.; Orwoll, Eric; Lin, Chung Yen; Chen, Shu Hwa; Shih, Shyang Rong; Lee, Cheng Han; Oda, Yoshinao; Billings, Steven D.; Li, Chien Feng; Nielsen, G. Petur; Konishi, Eiichi; Petersson, Fredrik; Carpenter, Thomas O.; Sittampalam, Kesavan; Huang, Hsuan Ying; Folpe, Andrew L.

In: Modern Pathology, 22.07.2016.

Research output: Contribution to journalArticle

Lee, JC, Su, SY, Changou, CA, Yang, RS, Tsai, KS, Collins, MT, Orwoll, E, Lin, CY, Chen, SH, Shih, SR, Lee, CH, Oda, Y, Billings, SD, Li, CF, Nielsen, GP, Konishi, E, Petersson, F, Carpenter, TO, Sittampalam, K, Huang, HY & Folpe, AL 2016, 'Characterization of FN1–FGFR1 and novel FN1–FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors', Modern Pathology. https://doi.org/10.1038/modpathol.2016.137
Lee, Jen Chieh ; Su, Sheng Yao ; Changou, Chun A. ; Yang, Rong Sen ; Tsai, Keh Sung ; Collins, Michael T. ; Orwoll, Eric ; Lin, Chung Yen ; Chen, Shu Hwa ; Shih, Shyang Rong ; Lee, Cheng Han ; Oda, Yoshinao ; Billings, Steven D. ; Li, Chien Feng ; Nielsen, G. Petur ; Konishi, Eiichi ; Petersson, Fredrik ; Carpenter, Thomas O. ; Sittampalam, Kesavan ; Huang, Hsuan Ying ; Folpe, Andrew L. / Characterization of FN1–FGFR1 and novel FN1–FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors. In: Modern Pathology. 2016.
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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.Modern Pathology advance online publication, 22 July 2016; doi:10.1038/modpathol.2016.137.",
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AU - Su, Sheng Yao

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AU - Yang, Rong Sen

AU - Tsai, Keh Sung

AU - Collins, Michael T.

AU - Orwoll, Eric

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AU - Chen, Shu Hwa

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AU - Lee, Cheng Han

AU - Oda, Yoshinao

AU - Billings, Steven D.

AU - Li, Chien Feng

AU - Nielsen, G. Petur

AU - Konishi, Eiichi

AU - Petersson, Fredrik

AU - Carpenter, Thomas O.

AU - Sittampalam, Kesavan

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N2 - 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.Modern Pathology advance online publication, 22 July 2016; doi:10.1038/modpathol.2016.137.

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