Frequent overexpression of klotho in fusion-negative phosphaturic mesenchymal tumors with tumorigenic implications

Lee, Cheng‐Han; Su, Sheng; Sittampalam, Kesavan; Chen, Paul Chih Hsueh; Petersson, Fredrik; Kao, Yu Chien; Carpenter, Thomas O.; Hsieh, Tsung Han; Konishi, Eiichi; Tsai, Jen Wei; Billings, Steven D.; Folpe, Andrew L.; Lee, Jen‐Chieh

doi:10.1038/s41379-019-0416-4

Cited by 20 publications

(25 citation statements)

References 37 publications

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“…This activity has been associated with early tumor reoccurrence [ 253 ]. Half of phosphaturic mesenchymal tumors lack FGFR1 fusions; however, Klotho-β overexpression in this subset has suggested that in the absence of FGFR1 fusion, FGFR signaling is still active through Klotho-β [ 254 ]. The FGF-FGFR signaling axis has a role in promoting EMT in MM [ 255 ].…”

Section: The Role Of Canonical Fgfr Cofactors In Cancermentioning

confidence: 99%

Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling

Ferguson

Smith

Francavilla

2021

Cells

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Increasing evidence indicates that success of targeted therapies in the treatment of cancer is context-dependent and is influenced by a complex crosstalk between signaling pathways and between cell types in the tumor. The Fibroblast Growth Factor (FGF)/FGF receptor (FGFR) signaling axis highlights the importance of such context-dependent signaling in cancer. Aberrant FGFR signaling has been characterized in almost all cancer types, most commonly non-small cell lung cancer (NSCLC), breast cancer, glioblastoma, prostate cancer and gastrointestinal cancer. This occurs primarily through amplification and over-expression of FGFR1 and FGFR2 resulting in ligand-independent activation. Mutations and translocations of FGFR1-4 are also identified in cancer. Canonical FGF-FGFR signaling is tightly regulated by ligand-receptor combinations as well as direct interactions with the FGFR coreceptors heparan sulfate proteoglycans (HSPGs) and Klotho. Noncanonical FGFR signaling partners have been implicated in differential regulation of FGFR signaling. FGFR directly interacts with cell adhesion molecules (CAMs) and extracellular matrix (ECM) proteins, contributing to invasive and migratory properties of cancer cells, whereas interactions with other receptor tyrosine kinases (RTKs) regulate angiogenic, resistance to therapy, and metastatic potential of cancer cells. The diversity in FGFR signaling partners supports a role for FGFR signaling in cancer, independent of genetic aberration.

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Section: The Role Of Canonical Fgfr Cofactors In Cancermentioning

confidence: 99%

Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling

Ferguson

Smith

Francavilla

2021

Cells

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“…Case 102 is the only case with FN1-FGFR2 characterized by RNA-seq previously (2). *PMTs = Phosphaturic Mesenchymal Tumors with FN1-FGFR1 fusions and range of breakpoints reported in the literature (3,12,25,27,28). *PAs = pleomorphic adenoma of salivary gland origin with FGFR1-PLAG1 fusions and range of breakpoints reported in the literature (40).…”

Section: Resultsmentioning

confidence: 99%

“…A significant subset of PMT was also shown to harbor FN1-FGFR1 fusions and are frequently associated with hypophosphatemia and tumor-induced osteomalacia secondary to paraneoplastic secretion of the fibroblast growth factor 23 (FGF23) (3,12). Examples of PMT without apparent tumor-induced osteomalacia, however, have also been described (24) as well as fusion-negative cases that frequently overexpress α-klotho, a transmembrane enzyme that acts as an FGF23 activator (25). α-Klotho interacts directly with FGFR1 and forms a high-affinity binding site at Ig3 domain for FGF23 (26).…”

Section: Discussionmentioning

confidence: 99%

Calcified chondroid mesenchymal neoplasms with FN1-receptor tyrosine kinase gene fusions including MERTK, TEK, FGFR2, and FGFR1: a molecular and clinicopathologic analysis

Liu

Wang

Yeh

et al. 2020

Preprint

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Translocations involving FN1 have been described in a variety of neoplasms, which share the presence of cartilage matrix and a variable extent of calcification. Fusions of FN1 to FGFR1 or FGFR2 have been reported in nine soft tissue chondromas, mostly demonstrated indirectly by FISH analysis. Delineation of FN1 fusions with various partner genes will facilitate our understanding of the pathogenesis and diagnostic classification of these neoplasms. In this study, we present molecular, clinical and pathologic features of 9 cartilaginous soft tissue neoplasms showing a predilection for the TMJ region and the extremities. We analyzed for gene fusions with precise breakpoints using targeted RNA-seq with a 115-gene panel, including FN1, FGFR1 and FGFR2. All 9 cases were positive for a gene fusion, including two novel fusions, FN1-MERTK and FN1-TEK, each in one case, recurrent FN1-FGFR2 in 5 cases, FN1-FGFR1 without the Ig3 domain in one case, and FGFR1-PLAG1 in one case. The breakpoints in the 5′ partner gene FN1 ranged from exons 11-48, retaining the domains of signal peptide, FN1, FN2, and/or FN3, while the 3 ′ partner genes retained the trans-membrane domain, tyrosine kinase domains and /or Ig domain. The tumors with FN1-FGFR1, FN1-FGFR2 and FN1-MERTK fusions are generally characterized by nodular/lobular growth of polygonal to stellate cells within a chondroid matrix, often accompanied by various patterns of calcification. These features resemble those as described for the chondroblastoma-like variant of soft tissue chondroma. Additional histologic findings include calcium pyrophosphate dehydrate deposition and features resembling tenosynovial giant cell tumor. Overall, while the tumors from our series show significant morphologic overlap with chondroblastoma-like soft tissue chondroma, we describe novel findings that expand the morphologic spectrum of these neoplasms and have therefore labeled them as calcified chondroid mesenchymal neoplasms. These neoplasms represent a distinct pathologic entity given the presence of recurrent FN1-receptor tyrosine kinase fusions.

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“…The patient was diagnosed and treated for hypophosphatemic rickets. There was no localizable PMT, yet, 30 years later, the patient developed two PMT in the mastoid bone [ 8 ]. The published reports and our case could imply that the association of PMT and HPT was not accidental, and perhaps, FGF23 per se or FGF23 pathway (including FGFR1-Klotho receptor) was the primary inducer of hyperparathyroidism.…”

Section: Discussionmentioning

confidence: 99%

TIO Associated with Hyperparathyroidism: A Rarity, a Rule, or a Novel HPT-PMT Syndrome—A Case Study with Literature Review

Salim

Behairy

Barengolts

2021

Case Reports in Endocrinology

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Objective. Association of primary hyperparathyroidism (pHPT) with phosphaturic mesenchymal tumors (PMT) is rarely reported. This report entertains the hypothesis of the causal association of HPT with tumor-induced osteomalacia (TIO) and of the existence of HPT-PMT syndrome. Case Presentation. A 49-year-old man presented with fragility rib fractures, generalized bone pain, and muscle weakness worsening over the past 3 years. Initial tests demonstrated hypophosphatemia and high PTH. The diagnosis of pHPT was entertained, but parathyroid scan was negative. During a 2-year follow-up, the patient reported minimal improvement of symptoms after intermittent treatment with calcitriol and phosphate. Biochemical evaluation showed persistent hypophosphatemia with renal phosphate wasting, elevated FGF23, and osteopenia on DXA scan. TIO was suspected. Multiple MRIs and whole-body FDG-PET scans were inconclusive. The patient subsequently underwent 68Ga-DOTATATE PET-CT, which revealed a somatostatin receptor-positive lesion in the lung. The resected mass was confirmed as PMT. The patient had dramatically improved symptoms, normal phosphate, calcium, and FGF23. During follow-up over 3 years postsurgery, the patient had slowly rising calcium and persistently elevated PTH. Conclusion. The debate whether the patient had pHPT or tertiary HPT prompted literature review showing that aberrant genes including FGFR1, FGF1, fibronectin 1, and Klotho were mechanistically involved in the HPT-PMT association. This case highlights the pitfalls contributing to delayed diagnosis and treatment of TIO and hypothesizes the association between pHPT and PMT.

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Frequent overexpression of klotho in fusion-negative phosphaturic mesenchymal tumors with tumorigenic implications

Cited by 20 publications

References 37 publications

Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling

Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling

Calcified chondroid mesenchymal neoplasms with FN1-receptor tyrosine kinase gene fusions including MERTK, TEK, FGFR2, and FGFR1: a molecular and clinicopathologic analysis

TIO Associated with Hyperparathyroidism: A Rarity, a Rule, or a Novel HPT-PMT Syndrome—A Case Study with Literature Review

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