Identification of a novelFN1-FGFR1genetic fusion as a frequent event in phosphaturic mesenchymal tumour

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.

Phosphaturic Mesenchymal Tumor Involving the Head and Neck: A Report of Five Cases with FGFR1 Fluorescence In Situ Hybridization Analysis

“…Patients with PMT often present with pain or weakness although the symptoms depend on the site affected and not all patients will develop osteomalacia. Recently, Lee and colleagues used RT-PCR in addition to FISH and Western blot analysis to demonstrate that nine of fifteen PMTs arising in non-head and neck sites harbored a translocation that resulted in a novel FN1-FGFR1 fusion protein [12]. This fusion protein is believed to cause the upregulation of the FGFR1 receptor.…”

“…High grade tumors need to be distinguished from chondrosarcoma and osteosarcoma and the pathologist is encouraged to look for better differentiated areas of the tumor with features more typical of PMT. In these cases, FISH for a FGFR1 translocation may be particularly useful [12].…”

“…The increased expression of FGF23 by neoplastic cells can be demonstrated in formalin-fixed, paraffin-embedded tissue by chromogenic in situ hybridization (CISH) [11]. In a subset of tumors, the overexpression of FGF23 is associated with a fibronectin-1-fibroblast growth factor receptor-1 (FN1-FGFR1) fusion that can be detected by reverse transcriptase polymerase chain reaction (RT-PCR) [12].…”

Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a multilineage somatic mosaic RASopathy

“…NVP-BGJ398, a pan-specific FGFR inhibitor, further ameliorated hypophosphatemia and improved calcitriol biosynthesis in the Hyp mouse model [35]. Moreover, a recent study of 14 phosphaturic mesenchymal tumors (PMT) demonstrated a fibronectin-FGFR1 (FN-FGFR1) fusion in 9 of them (9/14, 60%), implicating tumor-induced osteomalacia to be a consequence of FGFR1 overexpression [36]. It is thus possible that constitutively active RAS mutations, which drive downstream signaling of FGFR1, could also induce overproduction of FGF23.…”

Fusion Genes and their Detection through Next Generation Sequencing in Malignant Hematological Disease and Solid Tumors

“…A recurrent gene fusion, RPS6KB1 kinase, and EGFR, which is a therapeutically important receptor kinase and involving in the rapamycin signaling, was discovered in the analysis of 14 breast cancer cell lines [1]. Not only in common tumors, recent study also indicated a novel FN1-FGFR1 fusion gene might participate the tumorgenesis of phosphaturic mesenchymal tumors (PMTs), which typically cause hypophosphataemia and tumor-induced osteomalacia (TIO) [20].…”