Identification of a novel FN1-FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour

Jen Chieh Lee, Yung Ming Jeng, Sheng Yao Su, Chen Tu Wu, Keh Sung Tsai, Cheng Han Lee, Chung Yen Lin, Jodi M. Carter, Jenq Wen Huang, Shu Hwa Chen, Shyang Rong Shih, Adrián Mariño-Enríquez, Chih Chi Chen, Andrew L. Folpe, Yih Leong Chang, Cher Wei Liang

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54 Citations (Scopus)

Abstract

Phosphaturic mesenchymal tumours (PMTs) are uncommon soft tissue and bone tumours that typically cause hypophosphataemia and tumour-induced osteomalacia (TIO) through secretion of phosphatonins including fibroblast growth factor 23 (FGF23). PMT has recently been accepted by the World Health Organization as a formal tumour entity. The genetic basis and oncogenic pathways underlying its tumourigenesis remain obscure. In this study, we identified a novel FN1-FGFR1 fusion gene in three out of four PMTs by next-generation RNA sequencing. The fusion transcripts and proteins were subsequently confirmed with RT-PCR and western blotting. Fluorescence in situ hybridization analysis showed six cases with FN1-FGFR1 fusion out of an additional 11 PMTs. Overall, nine out of 15 PMTs (60%) harboured this fusion. The FN1 gene possibly provides its constitutively active promoter and the encoded protein's oligomerization domains to overexpress and facilitate the activation of the FGFR1 kinase domain. Interestingly, unlike the prototypical leukaemia-inducing FGFR1 fusion genes, which are ligand-independent, the FN1-FGFR1 chimeric protein was predicted to preserve its ligand-binding domains, suggesting an advantage of the presence of its ligands (such as FGF23 secreted at high levels by the tumour) in the activation of the chimeric receptor tyrosine kinase, thus effecting an autocrine or a paracrine mechanism of tumourigenesis.

Original languageEnglish
Pages (from-to)539-545
Number of pages7
JournalJournal of Pathology
Volume235
Issue number4
DOIs
Publication statusPublished - Mar 1 2015
Externally publishedYes

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Keywords

  • FGFR1
  • FN1
  • Phosphaturic mesenchymal tumour
  • RNA sequencing
  • Translocation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Lee, J. C., Jeng, Y. M., Su, S. Y., Wu, C. T., Tsai, K. S., Lee, C. H., Lin, C. Y., Carter, J. M., Huang, J. W., Chen, S. H., Shih, S. R., Mariño-Enríquez, A., Chen, C. C., Folpe, A. L., Chang, Y. L., & Liang, C. W. (2015). Identification of a novel FN1-FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour. Journal of Pathology, 235(4), 539-545. https://doi.org/10.1002/path.4465