IndraLab
Statements
sparser
"For example, an FN1‐FGFR1 fusion gene has been identified in several TIO tumors; this gene has been hypothesized to cause tumorigenesis in TIO through FGF23 binding, leading to autocrine or paracrine activation of the receptor tyrosine kinase. ( xref , xref ) Interestingly, FGFR1 fusion genes have been identified as pathogenic in the 8p11 myeloproliferative syndrome, breast cancer, glioblastoma, and lung squamous cell carcinoma. ( xref , xref ) Additionally, similar microRNA profiles were recently noted in osteosarcomas and TIO; both show upregulation of the biomarker miR‐197 and downregulation of miR‐20b, miR‐144, and miR‐335. ( xref ) Further genetic studies of TIO may improve our understanding of the disease and identify patients missed by currently available modalities."
sparser
"In order to continue improving TIO management in the future, there are several needs: (1) a clear algorithm for initial biochemical testing to support clinical suspicion; (2) better functional imaging; (3) clinically available testing that can differentiate patients with TIO from those with genetic causes—currently, negative genetic test results still do not completely rule out the possibility of genetic diseases; (4) development of improved surgical and other less invasive techniques, such as cryotherapy, radiofrequency therapy, and radiotherapy with somatostatin analogues, to achieve cure even when tumors are located near vital structures and/or remote locations; (5) direct comparison of the efficacy and safety of conventional therapy versus burosumab; (6) increased understanding of FGF23 levels in TIO and other hypophosphatemic disorders, in order to correctly diagnose TIO patients with inappropriately normal levels of FGF23 [ xref , xref ]; (7) more understanding of the FN1‐FGFR1 fusion gene effects in the pathogenesis of TIO and how to exploit it as a potential therapeutic target; (8) better understanding of severe myopathy seen in patients with TIO; and (9) increased understanding of the recurrent and malignant transformation of PMT."
sparser
"A relevant finding in understanding its tumorigenesis was the identification of fibronectin 1 ( FN1 ) and fibroblast growth factor receptor‐1 ( FGFR1 ) translocations which led to an FN1‐FGFR1 fusion protein in 60% of studied PMTs by RNA sequencing or FGFR‐specific fluorescence in situ hybridization (FISH). xref Additional studies have confirmed this finding in a larger group of PMTs. xref In addition to the description of the FN1‐FGFR1 translocation, it has been recently reported that 6% of PMTs had an FN1 ‐fibroblast growth factor 1 ( FGF1 ) translocation. xref However, these findings still suggest the existence of the tumorigenic drivers behind the fusion‐negative cases, and the mutational landscape and genetic signatures of PMTs are yet to be elucidated."
sparser
"A relevant finding in the study of PMT pathogenesis identified FN1 and FGFR1 translocations as a leading cause of FN1‐FGFR1 fusion protein in 60% of samples by RNA sequencing or fluorescence in situ hybridization (FISH). xref The FN1‐FGFR1 fusion gene would presumably be highly expressed since FN1 is an ubiquitously expressed extracellular protein and is driven by a strong promoter. xref In this way, FGF23 secretion would be up‐regulated to down‐regulate the levels of phosphate and other biomolecules associated with PMTs."
sparser
"Moreover, Fibronectin 1 (FN1) is a gene that is responsible for encoding a protein that also plays a major role in cell adhesion, growth, and differentiation. xref It is commonly associated with the development of various types of cancer including lung, breast, thyroid, and gastric. xref , xref The FN1–FGFR1 fusion protein (as seen in this patient’s molecular testing) is a hallmark driver of PMT."
sparser
"The most upstream breakpoint of FN1 gene was located at the 3' end of exon 12, and the most downstream breakpoint of FGFR1 gene was at the 5' end of exon 9, suggesting the inessential nature of the third fibronectin type domain of FN1, and the necessity of the transmembrane domain of FGFR1 in the FN1::FGFR1 fusion protein, respectively."
sparser
"It has been discussed that increased expression of the FN1–FGF1 fusion protein functions like FGF1 secreted at high levels, which would subsequently affect phosphorus metabolism. xref In the case of the FN1–FGFR1 fusion protein, previous studies have discussed that FN1–FGFR1 proteins could use the self-assembly and fibronectin-binding domains of FN1 to dimerize and achieve a ligand-independent activation of the FGFR1 domain. xref Examples of both the FN1–FGF1 and FN1–FGFR1 fusion proteins are displayed in."
sparser
"Chromosomal translocations resulting in a fibronectin 1‐FGFR1 (FN1/FGFR1) fusion gene have been identified in approximately 40% of resected PMTs. ( xref ) The fusion protein presumably includes the extracellular fibronectin autodimerization domain, and the FGFR1 ligand‐binding, transmembrane, and intracellular signaling domains, which would suggest that FGFR1 signaling may have a prominent role in tumorigenesis and FGF23 secretion, and thus be a therapeutic target in TIO. ( xref , xref ) "
sparser
"Reduced serum 1,25(OH) 2 D and elevated bone‐specific alkaline phosphatase can be used as diagnostic markers, and if measured, serum FGF23 is typically elevated. xref In a large TIO series, 48% of tumors exhibited evidence for translocations resulting in abnormal fusion proteins of fibronectin 1 (FN1) and either fibroblast growth factor receptor 1 (FGFR1) or fibroblast growth factor 1 (FGF1) (3/50 [6%] FN1‐FGFR1 and 21/50 [42%] FN1‐FGF1), hypothesized to generate an autocrine function loop. xref Complete removal of the tumor by wide resection or ablation is typically curative of the biochemical abnormalities with improvement in bone and muscle strength. xref However, these mesenchymal tumors are slow growing and may be difficult to localize."
sparser
"Our previous experience treating a patient with diffusely metastatic TIO with a known FN1‐FGFR1 fusion with infigratinib resulted in FGF23 suppression and normalization of phosphate, TRP, and 1,25D. Of note, a tumor adjacent to the scapula calcified during the first 3 months of infigratinib treatment."
sparser
"Although this fusion is unique, it likely results in increased activation of the FGFR1 pathway, similar to the FN1‐FGFR1 fusion. ( xref ) Recently, fusion‐negative PMTs have been found to have increased expressions of KL mRNA, which encodes alpha‐KLOTHO, the coreceptor for FGF23‐FGFR1 binding, hinting at a third possible mechanism for PMT tumorigenesis, upstream of the FGFR1 pathway. ( xref , xref ) All three mechanisms presumptively involve increased activation of FGFR1, causing PMT tumorigenesis and FGF23 excess."
sparser
"In tumors without FN1-FGFR1 or FN1-FGF1 translocations, ectopic expression of KL might be involved in the mechanisms underlying the oversecretion of FGF23 due to the putative autocrine action of FGF23 stimulating the KL/FGFR1 receptor complex in identical osteocyte-like cells, though a driver variant for ectopic expression of KL has not been identified [ xref , xref ]."
sparser
"TIO is caused by mesenchymal tumours often described as hemangioperitomas, which secrete FGF23 and cause a paraneoplastic renal phosphate wasting syndrome with osteomalacia and muscle weakness. ( xref ) RNA-seq analysis of FGF23-producing tumours revealed fibronectin (FN)- FGF1 or FN-FGFR1 gene rearrangements, which may activate FGFR1 in an autocrine fashion that stimulates FGF23 production by these tumours. ( xref ) Increased KL expression may constitute a second positive feedback loop to increase FGF23 production in TIO tumours, suggesting that the autocrine stimulation of FGF23 and the manifestations of TIO may be KL-dependent, however this requires further study. ( xref )"
sparser
"While the currently described patient is PTEN mutation-negative, high levels of phosphorylated AKT and phosphorylated S6 were detected on immunohistochemical staining (data not shown), supporting the concept that the AKT pathway is activated in tumor cells, perhaps due to translocation-mediated signaling through the chimeric FN1-FGFR1 receptor."
sparser
"By FN1 break-apart FISH and reappraisal of previous RNA sequencing data, 6 tumors previously considered "fusion-negative" (defined by negative results of FISH for FN1::FGFR1 fusion and FGF1 break-apart and/or of RNA sequencing) were reclassified as fusion-positive PMTs, including one containing a novel FN1::ZACN fusion."
sparser
"Finally, driven by our impression that soft tissue chondroma with grungy calcification shared histological similarities with phosphaturic mesenchymal tumours, known to harbour FN1-FGFR1 , and FN1-FGF1 fusion genes ( xref ), we speculated that both genes represented candidate fusion genes partners in soft tissue chondromas."
sparser
"In view of an FN1-FGFR1 fusion gene being characteristic of phosphaturic mesenchymal tumour and typically expressing high levels of FGF23 we investigated the gene expression using RNA in situ hybridisation (RNAscope) and qPCR in eight soft tissue chondromas eight cases showing a FN1 break-apart signal of our series."
sparser
"Specifically, fusion of fibronectin 1 (FN1) with FGFR1 or FGF1 creates aberrant fusion genes FN1-FGFR1 and FN1-FGF1, which are overexpressed in 42% and 6% of PMT, respectively [ xref ], while aberrant α -Klotho (or less commonly β -Klotho) genes are overexpressed in 8 of 10 fusion-negative PMT [ xref ]."