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

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 Organiza...

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Published in:	The Journal of pathology Vol. 235; no. 4; pp. 539 - 545
Main Authors:	Lee, Jen-Chieh, Jeng, Yung-Ming, Su, Sheng-Yao, Wu, Chen-Tu, Tsai, Keh-Sung, Lee, Cheng-Han, Lin, Chung-Yen, Carter, Jodi M, Huang, Jenq-Wen, Chen, Shu-Hwa, Shih, Shyang-Rong, Mariño-Enríquez, Adrián, Chen, Chih-Chi, Folpe, Andrew L, Chang, Yih-Leong, Liang, Cher-Wei
Format:	Journal Article
Language:	English
Published:	Chichester, UK John Wiley & Sons, Ltd 01-03-2015 Wiley Subscription Services, Inc
Subjects:	Adult Aged Biomarkers, Tumor - analysis Biomarkers, Tumor - genetics Blotting, Western Female FGFR1 Fibronectins - analysis Fibronectins - genetics FN1 Gene Fusion High-Throughput Nucleotide Sequencing Humans Hypophosphatemia, Familial - etiology In Situ Hybridization, Fluorescence Male Middle Aged Neoplasms, Connective Tissue - chemistry Neoplasms, Connective Tissue - complications Neoplasms, Connective Tissue - genetics Neoplasms, Connective Tissue - pathology phosphaturic mesenchymal tumour Receptor, Fibroblast Growth Factor, Type 1 - analysis Receptor, Fibroblast Growth Factor, Type 1 - genetics Reverse Transcriptase Polymerase Chain Reaction RNA sequencing translocation RNA sequencing FN1 translocation phosphaturic mesenchymal tumour FGFR1
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Summary:	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. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Bibliography:	istex:4B944994ED8AD13EE6D4B4F2BFB497C9AB0EFCD5 Supporting InformationFigure S1 Heatmap plot with hierarchical clustering analysis of the expression levels of the 31 genes in 4 PMTs and 28 non-PMT tumours derived from RNA sequencing data. The FPKM values of respective genes with logn transformation were used to generate this heatmap; FPKM values of 0 were re-assigned as 10−4 so they became amenable to logn transformation yet still smaller than the smallest non-zero FPKM value (2.6 x 10−3). Note that all 4 PMTs clustered together and expressed high levels of FGFR1, FGF1, FGF23, MEPE and SFRP4, as well as low levels of KL. Check Table S1 for the abbreviations of tumour types.Figure S2 EdgeR MDS plot (first) and DeSeq PCA plot (second) of the PMT-1, PMT-2, and the 28 non-PMT tumour samples. After filtering out genes with low expression levels, 16709 genes were left for the analyses. The mesenchymal tumours were separated from the carcinomas, while PMT-1 and PMT-2 clustered together.Figure S3 RT-PCR (composited according to the markers) and DNA PCR. Check supplementary Table S2 for the primer sequences and combination sets. (T, tumour; C or Control, control PCR using no input nucleic acid). Note that the presumed reciprocal fusion gene (5'FGFR1-3'FN1) was not amplified in DNA PCR (primer sets #3, #4, #7, and #8).Figure S4 Illustration of chromosomal rearrangement resulting in FN1-FGFR1 fusion. The fusion partners, 5'-FN1 and 3'-FGFR1, were telomeric in direction on chromosome 2q and 8p, respectively. The derivative chromosome containing FN1(5')-FGFR1(3') resulting from simple reciprocal translocation is predicted to lose the centromere. The rearrangement in PMTs may, therefore, more likely take other forms, such as insertion of one partner gene into the other.Table S1 List of the samples of which the RNA sequencing data were comparedTable S2 Sequences of primers used in DNA PCR and RT-PCRTable S3 Fusion detection in PMTsTable S4 PMT gene expression (FPKM values) and ranking by RNA sequencing ArticleID:PATH4465 ark:/67375/WNG-W6M3M0JR-9 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-3417 1096-9896
DOI:	10.1002/path.4465