A single primary cilium projects from most vertebrate cells to guide cell fate decisions. A growing list of signaling molecules is found to function through cilia and control ciliogenesis, including the fibroblast growth factor receptors (FGFR). Aberrant FGFR activity produces abnormal cilia with deregulated signaling, which contributes to pathogenesis of the FGFR-mediated genetic disorders. FGFR lesions are also found in cancer, raising a possibility of cilia involvement in the neoplastic transformation and tumor progression. Here, we focus on FGFR gene fusions, and discuss the possible mechanisms by which they function as oncogenic drivers. We show that a substantial portion of the FGFR fusion partners are proteins associated with the centrosome cycle, including organization of the mitotic spindle and ciliogenesis. The functions of centrosome proteins are often lost with the gene fusion, leading to haploinsufficiency that induces cilia loss and deregulated cell division. We speculate that this complements the ectopic FGFR activity and drives the FGFR fusion cancers.

• Klíčová slova
• FGFR, FGFR fusion, cancer, centrosome, centrosome cycle, cilia, fibroblast growth factor receptor, neoplastic transformation, oncogenic driver, primary cilia,
• MeSH
• centrozom metabolismus   MeSH
• cilie * metabolismus   patologie   MeSH
• lidé MeSH
• nádorová transformace buněk patologie   MeSH
• nádory * metabolismus   patologie   MeSH
• onkogenní fúze MeSH
• receptory fibroblastových růstových faktorů metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• receptory fibroblastových růstových faktorů MeSH

The onset of routine use of the next generation sequencing (NGS) leads to discovery of new mutations in non-small cell lung cancer (NSCLC). In addition, comprehension of therapeutic potential of these genetic alterations in clinical practice is needed and required. Both, rare mutations and the therapeutic considerations they prompt, are dealt with in our case report describing a new fusion mutation of the fibroblast growth factor receptor (FGFR). Our case report describes a 45-year Caucasian female, non-smoker, with the tyrosine-protein kinase Met (cMET) skip 14 mutation and a newly described fibroblast growth factor receptor-cholinergic receptor, nicotinic, alpha 6 (FGFR-CHNRA6) fusion. The tumor in this patient showed aggressive growth and was resistant to all treatment modalities administered (including combination chemotherapy with bevacizumab, pemetrexed and nintedanib), with the exception of very short efficacy of crizotinib. The patient died 5 months after diagnosis. According to the published literature, a theoretical future solution could be to administer multidimensional targeted therapy simultaneously.

• Klíčová slova
• Fibroblast growth factor receptor (FGFR), cMET, case report, crizotinib, nintedanib,
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

The FGFR3::TACC3 fusion has been reported in subsets of diverse cancers including urothelial and squamous cell carcinomas (SCC). However, the morphology of FGFR3::TACC3-positive head and neck carcinomas has not been well studied and it is unclear if this fusion represents a random event, or if it might characterize a morphologically distinct tumor type. We describe nine FGFR3::TACC3 fusion-positive head and neck carcinomas affecting six males and three females aged 38 to 89 years (median, 59). The tumors originated in the sinonasal tract (n = 4), parotid gland (n = 2), and one case each in the oropharynx, submandibular gland, and larynx. At last follow-up (9-21 months; median, 11), four patients developed local recurrence and/or distant metastases, two died of disease at 11 and 12 months, one died of other cause, one was alive with disease, and two were disease-free. Three of six tumors harbored high risk oncogenic HPV infection (HPV33, HPV18, one unspecified). Histologically, three tumors revealed non-keratinizing transitional cell-like or non-descript morphology with variable mixed inflammatory infiltrate reminiscent of mucoepidermoid or DEK::AFF2 carcinoma (all were HPV-negative), and three were HPV-associated (all sinonasal) with multiphenotypic (1) and non-intestinal adenocarcinoma (2) pattern, respectively. One salivary gland tumor showed poorly cohesive large epithelioid cells with prominent background inflammation and expressed AR and GATA3, in line with a possible salivary duct carcinoma variant. Two tumors were conventional SCC. Targeted RNA sequencing revealed an in-frame FGFR3::TACC3 fusion in all cases. This series highlights heterogeneity of head and neck carcinomas harboring FGFR3::TACC3 fusions, which segregates into three categories: (1) unclassified HPV-negative category, morphologically distinct from SCC and other entities; (2) heterogeneous group of HPV-associated carcinomas; and (3) conventional SCC. A driver role of the FGFR3::TACC3 fusion in the first category (as a potential distinct entity) remains to be further studied. In the light of available FGFR-targeting therapies, delineation of these tumors and enhanced recognition is recommended.

• Klíčová slova
• FGFR, Gene fusions, RNA sequencing, Sinonasal, Targeted therapy, Tyrosine kinase inhibitor,
• MeSH
• dlaždicobuněčné karcinomy hlavy a krku MeSH
• dospělí MeSH
• fenotyp MeSH
• fúzní onkogenní proteiny * genetika   MeSH
• infekce papilomavirem * komplikace   virologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery * genetika   analýza   MeSH
• nádory hlavy a krku * genetika   patologie   virologie   MeSH
• proteiny asociované s mikrotubuly MeSH
• receptor fibroblastových růstových faktorů, typ 3 * genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• spinocelulární karcinom * genetika   patologie   virologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• FGFR3 protein, human MeSH Prohlížeč
• fúzní onkogenní proteiny * MeSH
• nádorové biomarkery * MeSH
• proteiny asociované s mikrotubuly MeSH
• receptor fibroblastových růstových faktorů, typ 3 * MeSH
• TACC3 protein, human MeSH Prohlížeč

BACKGROUND/AIM: Gliomas are primary malignancies of the central nervous system (CNS). High-grade gliomas are associated with poor prognosis and modest survival rates despite intensive multimodal treatment strategies. Targeting gene fusions is an emerging therapeutic approach for gliomas that allows application of personalized medicine principles. The aim of this study was to identify detectable fusion oncogenes that could serve as predictors of currently available or newly developed targeted therapeutics in cross-sectional samples from glioma patients using next-generation sequencing (NGS). PATIENTS AND METHODS: A total of 637 patients with glial and glioneuronal tumours of the CNS who underwent tumour resection between 2017 and 2020 were enrolled. Detection of fusion transcripts in FFPE tumour tissue was performed by a TruSight Tumour 170 assay and two FusionPlex kits, Solid Tumour and Comprehensive Thyroid and Lung. RESULTS: Oncogene fusions were identified in 33 patients. The most common fusion was the KIAA1549-BRAF fusion, detected in 13 patients, followed by FGFR fusions (FGFR1-TACC1, FGFR2-CTNNA3, FGFR3-TACC3, FGFR3-CKAP5, FGFR3-AMBRA1), identified in 10 patients. Other oncogene fusions were also infrequently diagnosed, including MET fusions (SRPK2-MET and PTPRZ1-MET) in 2 patients, C11orf95-RELA fusions in 2 patients, EGFR-SEPT14 fusion in 2 patients, and individual cases of SRGAP3-BRAF, RAF1-TRIM2, EWSR1-PALGL1 and TERT-ALK fusions. CONCLUSION: The introduction of NGS techniques provides additional information about tumour molecular alterations that can aid the multimodal management of glioma patients. Patients with gliomas positive for particular targetable gene fusions may benefit from experimental therapeutics, enhancing their quality of life and prolonging survival rates.

• Klíčová slova
• Glioma, gene fusion, molecular genetics, next-generation sequencing, targeted therapy,
• MeSH
• adaptorové proteiny signální transdukční genetika   MeSH
• gliom * genetika   patologie   MeSH
• kvalita života MeSH
• lidé MeSH
• onkogenní fúze * MeSH
• onkogeny genetika   MeSH
• protein-serin-threoninkinasy MeSH
• proteiny asociované s mikrotubuly genetika   MeSH
• průřezové studie MeSH
• tyrosinfosfatasy receptorového typu, třída 5 genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• AMBRA1 protein, human MeSH Prohlížeč
• protein-serin-threoninkinasy MeSH
• proteiny asociované s mikrotubuly MeSH
• PTPRZ1 protein, human MeSH Prohlížeč
• SRPK2 protein, human MeSH Prohlížeč
• TACC3 protein, human MeSH Prohlížeč
• tyrosinfosfatasy receptorového typu, třída 5 MeSH

Previously, we showed that expression of myeloma-associated (proto)oncogene fibroblast growth factor receptor 3 (FGFR-3) is increased in white blood cells from patients with chronic myeloid leukemia (CML). The abnormal expression was returned back to the normal levels as soon as these patients reconstituted their hematopoiesis following transplantation of allogeneic peripheral blood stem cells. The aims of this study were: (1) to define population(s) of cells overexpressing FGFR-3, and (2) to determine the expression of FGFR-3 during the clinical course of the disease. We show that the vast majority of FGFR-3 transcripts as well as FGFR-3 protein arise from CD34+ BCR-ABL+ cells. Although increased levels of FGFR-3 were found in majority of late chronic phase patients treated with interferon alpha or hydroxyurea, the expression of FGFR-3 was always lowered following treatment with BCR-ABL tyrosine kinase inhibitor STI571. Compared to unstimulated cells, high levels of FGFR-3 were also identified in CD34+ cells from granulocyte colony-stimulating factor-mobilized blood stem cell harvests from healthy donors, suggesting a potential growth factor-dependent basis for elevated expression of FGFR-3 in CML. These findings have implications for the involvement of FGFR-3 in malignant hematopoiesis and depict FGFR-3 tyrosine kinase in CD34+ leukemic cells as a possible target for tyrosine kinase inhibitors.

• MeSH
• antigeny CD34 analýza   MeSH
• bcr-abl fúzní proteiny genetika   MeSH
• buněčná diferenciace MeSH
• buněčné dělení MeSH
• chronická myeloidní leukemie genetika   patologie   patofyziologie   MeSH
• faktor stimulující kolonie granulocytů farmakologie   MeSH
• hematopoetické kmenové buňky chemie   cytologie   MeSH
• hematopoéza MeSH
• lidé MeSH
• protoonkogen Mas MeSH
• průtoková cytometrie MeSH
• receptor fibroblastových růstových faktorů, typ 3 MeSH
• receptory fibroblastových růstových faktorů genetika   MeSH
• regulace genové exprese u leukemie účinky léků   MeSH
• transplantace hematopoetických kmenových buněk MeSH
• tyrosinkinasy * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD34 MeSH
• bcr-abl fúzní proteiny MeSH
• faktor stimulující kolonie granulocytů MeSH
• FGFR3 protein, human MeSH Prohlížeč
• MAS1 protein, human MeSH Prohlížeč
• protoonkogen Mas MeSH
• receptor fibroblastových růstových faktorů, typ 3 MeSH
• receptory fibroblastových růstových faktorů MeSH
• tyrosinkinasy * MeSH

The fibroblast growth factor receptors (FGFRs) are important oncogenes promoting tumor progression in many types of cancer, such as breast, bladder, and lung cancer as well as multiple myeloma and rhabdomyosarcoma. However, little is known about how these receptors are internalized and down-regulated in cells. We have here applied proximity biotin labeling to identify proteins involved in FGFR4 signaling and trafficking. For this purpose we fused a mutated biotin ligase, BirA*, to the C-terminal tail of FGFR4 (FGFR4-BirA*) and the fusion protein was stably expressed in U2OS cells. Upon addition of biotin to these cells, proteins in proximity to the FGFR4-BirA* fusion protein became biotinylated and could be isolated and identified by quantitative mass spectrometry. We identified in total 291 proteins, including 80 proteins that were enriched in samples where the receptor was activated by the ligand (FGF1), among them several proteins previously found to be involved in FGFR signaling (e.g., FRS2, PLCγ, RSK2 and NCK2). Interestingly, many of the identified proteins were implicated in endosomal transport, and by precise annotation we were able to trace the intracellular pathways of activated FGFR4. Validating the data by confocal and three-dimensional structured illumination microscopy analysis, we concluded that FGFR4 uses clathrin-mediated endocytosis for internalization and is further sorted from early endosomes to the recycling compartment and the trans-Golgi network. Depletion of cells for clathrin heavy chain led to accumulation of FGFR4 at the cell surface and increased levels of active FGFR4 and PLCγ, while AKT and ERK signaling was diminished, demonstrating that functional clathrin-mediated endocytosis is required for proper FGFR4 signaling. Thus, this study reveals proteins and pathways involved in FGFR4 transport and signaling that provide possible targets and opportunities for therapeutic intervention in FGFR4 aberrant cancer.

• Klíčová slova
• BioID, FGF1, FGFR4, clathrin, confocal microscopy, endocytosis, quantitative MS, recycling compartment, three-dimensional structured illumination microscopy, trans-Golgi network,
• MeSH
• barvení a značení MeSH
• biotinylace MeSH
• endocytóza MeSH
• endozomy metabolismus   MeSH
• klathrin metabolismus   MeSH
• lidé MeSH
• mikroskopie metody   MeSH
• nádorové buněčné linie MeSH
• receptor fibroblastových růstových faktorů, typ 4 metabolismus   MeSH
• signální transdukce MeSH
• trans-Golgiho síť metabolismus   MeSH
• transport proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• FGFR4 protein, human MeSH Prohlížeč
• klathrin MeSH
• receptor fibroblastových růstových faktorů, typ 4 MeSH