RESUMO
There is limited research on the clinicopathological characteristics of combined hepatocellular-cholangiocarcinoma (cHCC-CCA) currently. The aim of this study is to summerize the clinicopathological factors and prognosis of cHCC-CCA, which could help us understand this disease. 72 cases of cHCC-CCA from West China Hospital of Sichuan University were collected. Tissue components were reviewed by pathologists. Immunohistochemistry was used to detect the status of mismatch repair (MMR) and human epidermal growth factor receptor 2 (HER2) in cHCC-CCA, as well as the quantity and distribution of CD3+ T cells and CD8+ T cells. Fluorescence in situ hybridization was used to detect fibroblast growth factor receptor 2 (FGFR2) gene alteration. COX univariate and multivariate analyses were used to evaluate risk factors, and survival curves were plotted. 49 cases were classified as classic type cHCC-CCA and 23 cases as intermediate cell carcinoma. The cut-off value for diagnosing classic type was determined to be ≥ 30% for the cholangiocarcinoma component based on prognostic calculations. All tumors were MMR proficient. The rate of strong HER2 protein expression (3+) was 8.3%, and the frequency of FGFR2 gene alteration was 26.4%. CD3+ T cells and CD8+ T cells were mainly distributed at the tumor margin, and were protective factors for patients with cHCC-CCA. The overall survival of the 72 patients was 18.9 months, with a median survival of 12 months. Tumor size, TNM stage, and serum AFP level were prognostic factors for cHCC-CCA. The proportion of cholangiocarcinoma component reaching the threshold of 30%, may provide a reference for future pathology diagnosis. FGFR2 gene alteration was 26.4%, providing a clue for anti-FGFR2 therapy. However, more data is needed for further verification.
Assuntos
Neoplasias dos Ductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Neoplasias Hepáticas , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Humanos , Colangiocarcinoma/patologia , Colangiocarcinoma/genética , Colangiocarcinoma/mortalidade , Colangiocarcinoma/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Idoso , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/diagnóstico , Adulto , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Biomarcadores Tumorais/genética , Reparo de Erro de Pareamento de DNA , Imuno-HistoquímicaAssuntos
Síndrome Mão-Pé , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Humanos , Síndrome Mão-Pé/etiologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Feminino , Tiofenos/efeitos adversos , Tiofenos/uso terapêutico , Pessoa de Meia-Idade , Pirazóis , QuinoxalinasRESUMO
Offspring growth requires establishing maternal behavior associated with the maternal endocrine profile. Placentae support the adaptations of the mother, producing bioactive molecules that affect maternal organs. We recently reported that placentae produce superoxide dismutase 3 (SOD3) that exerts sustained effects on the offspring liver via epigenetic modifications. Here, we demonstrate that placenta-specific Sod3 knockout (Sod3-/-) dams exhibited impaired maternal behavior and decreased prolactin levels. Most fibroblast growth factor (FGF)-regulated pathways were downregulated in the pituitary tissues from Sod3-/- dams. FGF1-, FGF2-, and FGF4-induced prolactin expression and signaling via the phosphoinositide 3-kinase (PI3K)-phospholipase C-γ1 (PLCγ1)-protein kinase-Cδ (PKC)δ axis were reduced in primary pituitary cells from Sod3-/- dams. Mechanistically, FGF1/FGF receptor (FGFR)2 expressions were inhibited by the suppression of the ten-eleven translocation (TET)/isocitrate dehydrogenase (IDH)/α-ketoglutarate pathway and DNA demethylation levels at the zinc finger and BTB domain containing 18 (ZBTB18)-targeted promoters of Fgf1/Fgfr2. Importantly, offspring from Sod3-/- dams also showed impaired nurturing behavior to their grandoffspring. Collectively, placenta-derived SOD3 promotes maternal behavior via epigenetic programming of the FGF/FGFR-prolactin axis.
Assuntos
Fatores de Crescimento de Fibroblastos , Placenta , Prolactina , Transdução de Sinais , Superóxido Dismutase , Animais , Feminino , Gravidez , Placenta/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Camundongos , Superóxido Dismutase/metabolismo , Superóxido Dismutase/genética , Prolactina/metabolismo , Comportamento Materno , Camundongos Knockout , Hipófise/metabolismo , Deleção de Genes , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Camundongos Endogâmicos C57BLRESUMO
Pelvic organ prolapse (POP) affects approximately 40% of elderly women, characterized by the descent of the pelvic organs into the vaginal cavity. Here we present the results of a genome-wide association study (GWAS) for susceptibility to POP comprising 771 cases and 76,625 controls in the Japanese population. We identified a significant association of WT1 locus with POP in the Japanese population; rs10742277; odds ratio (OR) = 1.48, 95% confidence interval (CI), 1.29-1.68, P = 6.72 × 10-9. Subsequent cross-ancestry GWAS meta-analysis combining the Japanese data and previously reported European data, including 28,857 cases and 622,916 controls, identified FGFR2 locus as a novel susceptibility locus to POP (rs7072877; OR = 1.06, 95% CI, 1.04-1.08, P = 4.11 × 10-8). We also observed consistent directions of the effects for 21 out of 24 European GWAS derived loci (binomial test P = 2.8 × 10-4), indicating that most of susceptibility loci for POP are shared across the Japanese and European populations.
Assuntos
Predisposição Genética para Doença , Prolapso de Órgão Pélvico , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Povo Asiático/genética , Estudos de Casos e Controles , População do Leste Asiático , Estudo de Associação Genômica Ampla , Japão/epidemiologia , Prolapso de Órgão Pélvico/genética , Prolapso de Órgão Pélvico/epidemiologia , Polimorfismo de Nucleotídeo Único , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
Despite numerous efforts to develop FGFR inhibitors for cancer treatment, the widespread clinical application of currently available FGFR inhibitors has been significantly limited due to the serious side effects caused by poor selectivity and resistance. PROTAC technology, a method for protein degradation, has shown notable advantages over conventional inhibitors. In our study, we coupled Erdafitinib, a pan-FGFR inhibitor, with a CRBN binder to synthesize and identify an effective FGFR2 degrader, N5. Our findings demonstrated that N5 displayed notable specificity for FGFR2 and outstanding enzyme inhibitory capabilities, achieving an IC50 value of 0.08 nM against FGFR2, and strong antiproliferative activity, maintaining an inhibitory rate above 50% on gastric cancer cells at a concentration of 0.17 nM. Mechanistically, N5 induced gastric cancer cell cycle arrest at the G0/G1 phase and apoptosis by decreasing the levels of FGFR downstream proteins. Moreover, N5 demonstrated favorable pharmacokinetic characteristics with a bioavailability of 74.8% when administered intraperitoneally and effectively suppressed the growth of SNU16 xenograft tumors, exhibiting greater potency compared to the parental inhibitor Erdafitinib. This study lays the groundwork for developing and potentially applying therapeutic agents targeting FGFR2 degradation.
Assuntos
Antineoplásicos , Proliferação de Células , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Neoplasias Gástricas , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Animais , Relação Estrutura-Atividade , Camundongos , Apoptose/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Relação Dose-Resposta a Droga , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Linhagem Celular Tumoral , Camundongos Nus , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Neoplasias Experimentais/metabolismo , Proteólise/efeitos dos fármacos , QuinoxalinasRESUMO
BACKGROUND: Incidence of Crouzon syndrome is 1 per 25.000-31.000 newborns. This syndrome is extremely rarely accompanied by optic canal stenosis. OBJECTIVE: To present a patient with Crouzon syndrome and optic canal stenosis, to discuss the management of such patients considering own and literature data. MATERIAL AND METHODS: A 6-year-old boy presented with Crouzon syndrome (verified by molecular genetic research, i.e. FGFR2 gene mutation). The patient underwent 3 surgeries for craniosynostosis and hydrocephalus. Nevertheless, visual acuity progressively decreased despite patent ventriculoperitoneal shunt. Examination revealed severe decrease in visual functions with optic disc congestion under secondary atrophy. MRI data on subarachnoid CSF accumulation over both optic nerves potentially indicated optic canal stenosis. This assumption was confirmed by 3D CT. RESULTS: The patient underwent decompression of both optic canals with subsequent improvement of visual functions. CONCLUSION: Vision decrease following Crouzon syndrome may be due to optic canal stenosis. Decompression may be effective, even in long-term course of disease, and improve visual functions.
Assuntos
Disostose Craniofacial , Humanos , Masculino , Disostose Craniofacial/cirurgia , Disostose Craniofacial/complicações , Criança , Constrição Patológica/cirurgia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
Crouzon syndrome (CS), a syndromic craniosynostosis, is a craniofacial developmental deformity caused by mutations in fibroblast growth factor receptor 2 (FGFR2). Previous CS mouse models constructed using traditional gene editing techniques faced issues such as low targeting efficiency, extended lineage cycles, and inconsistent and unstable phenotypes. In this study, a CRISPR/Cas9-mediated strategy was employed to induce a functional augmentation of the Fgfr2 point mutation in mice. Various techniques, including bone staining, micro-CT, histological methods, and behavioral experiments, were employed to systematically examine and corroborate phenotypic disparities between mutant mice (Fgfr2C361Y/+) and their wild-type littermates. Confirmed via PCR-Sanger sequencing, we successfully induced the p.Cys361Tyr missense mutation in the Fgfr2 IIIc isoform of the extracellular domain (corresponding to the p.Cys342Tyr mutation in humans) based on Fgfr2-215 transcript (ENSMUST00000122054.8). Fgfr2C361Y/+ mice exhibited characteristics consistent with the phenotypic features associated with CS, including skull-vault craniosynostosis, skull deformity, shallow orbits accompanied by exophthalmos, midface hypoplasia with malocclusion, and shortened skull base, notably without any apparent limb defects. Furthermore, mutant mice displayed behavioral abnormalities encompassing deficits in learning and memory, social interaction, and motor dysfunction, without anxiety-related disorders. Histopathological examination of the hippocampal region revealed structural abnormalities, suggesting possible brain development impairment secondary to craniosynostosis. In conclusion, we constructed a novel gene-edited Fgfr2C361Y/+ mice strain based on CRISPR/Cas9, which displayed skull and behavioral abnormalities, serving as a new model for studying genetic molecular mechanisms and exploring treatments for CS. KEY MESSAGES: CRISPR/Cas9 crafted a Crouzon model by enhancing Fgfr2-C361Y in mice. Fgfr2C361Y/+ mice replicate CS phenotypes-craniosynostosis and midface anomalies. Mutant mice show diverse behavioral abnormalities, impacting learning and memory. Fgfr2C361Y/+ mice offer a novel model for cranial suture studies and therapeutic exploration.
Assuntos
Sistemas CRISPR-Cas , Disostose Craniofacial , Modelos Animais de Doenças , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Crânio , Animais , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Disostose Craniofacial/genética , Camundongos , Crânio/anormalidades , Crânio/patologia , Fenótipo , Comportamento Animal , Edição de Genes , Masculino , FemininoRESUMO
Developing new therapeutic strategies to target specific molecular pathways has become a primary focus in modern drug discovery science. Fibroblast growth factor receptor 2 (FGFR2) is a critical signaling protein involved in various cellular processes and implicated in numerous diseases, including cancer. Existing FGFR2 inhibitors face limitations like drug resistance and specificity issues. In this study, we present an integrated structure-based bioinformatics analysis to explore the potential of FGFR2 inhibitors-like compounds from the PubChem database with the Tanimoto threshold of 80%. We conducted a structure-based virtual screening approach on a dataset comprising 2336 compounds sourced from the PubChem database. Primarily, the selection of promising compounds was based on several criteria, such as drug-likeness, binding affinities, docking scores, and selectivity. Further, we conducted all-atom molecular dynamics (MD) simulations for 200 ns, followed by an essential dynamics analysis. Finally, a promising FGFR2 inhibitor with PubChem CID:507883 (1-[7-(1H-benzimidazol-2-yl)-4-fluoro-1H-indol-3-yl]-2-(4-benzoylpiperazin-1-yl)ethane-1,2-dione) was screened out from the study. This compound indicates a higher potential for inhibiting FGFR2 than the control inhibitor, Zoligratinib. The identified compound, CID:507883 shows >80% structural similarity with Zoligratinib. ADMET analysis showed promising pharmacokinetic potential of the screened compound. Overall, the findings indicate that the compound CID:507883 may have promising potential to serve as a lead candidate against FGFR2 and could be further exploited in therapeutic development.
Assuntos
Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/química , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Humanos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Ligação Proteica , Desenvolvimento de Medicamentos , Relação Estrutura-AtividadeRESUMO
PURPOSE: Early-onset biliary tract cancer (eoBTC) is among the fast-growing subset of early-onset cancers, yet little is known about its biology. We sought to identify novel molecular characteristics of eoBTC in relation to average-onset BTC (aoBTC) using a real-world multiomics data set. METHODS: The study comprised patients with BTC whose tumors underwent molecular analyses at Caris Life Sciences and were categorized by age (<50 years for eoBTC, ≥50 years for aoBTC). P values were adjusted for multiple testing and considered significant at Q < 0.05 (molecular comparisons) or Q < 0.25 (Gene Set Enrichment Analysis [GSEA]). Insurance claims data were used for survival analysis. RESULTS: The study included 5,587 patients with BTC (453 eoBTC, median age = 44 years and 5,134 aoBTC, median age = 68 years). FGFR2 fusion (15.7% in eoBTC v 5.9% in aoBTC) and NIPBL fusion (1.1% v 0%) were significantly more prevalent in eoBTC (both Q < 0.001). The interferon gamma-IFG score (fold change [FC], 1.1; Q = 0.01) and T-cell inflammation score (FC, 17.3; Q = 0.03) were significantly higher in aoBTC. On GSEA, angiogenesis was enriched in eoBTC (normalized enrichment score [NES] = 1.51; Q = 0.16), whereas IFG (NES = -1.58; Q = 0.06) and inflammatory response (NES = -1.46; Q = 0.18) were enriched in aoBTC. The median overall survival (OS) was 16.5 (eoBTC) versus 13.3 months (aoBTC), hazard ratio = 0.86, P = .004. The median OS by FGFR2 fusion (with fusion v without) was 21.7 versus 15.0 months (P = .47) for eoBTC and 18.6 versus 12.2 months (P < .001) for aoBTC. CONCLUSION: We identified crucial differences including higher prevalence of FGFR2 fusions in eoBTC and variations in immunotherapy-related markers. Better outcomes in eoBTC were affected by the FGFR2 fusion status. Our findings underscore the need for ensuring access to next-generation sequencing testing, including prompt identification of actionable targets.
Assuntos
Neoplasias do Sistema Biliar , Humanos , Neoplasias do Sistema Biliar/genética , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Idade de Início , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
Gastric cancer (GC) represents a major global health challenge as a highly prevalent disease with high mortality whose global incidence and mortality are predicted to worsen over the coming years. To date, our standard of care for advanced gastric cancer of combination chemotherapy and immunotherapy has a 1-year overall survival rate of 55%. Significant efforts have gone into identifying targetable alterations in gastric cancer, ultimately yielding the Fibroblast Growth Factor Receptors (FGFRs) family, specifically FGFR2 as a promising target. FGFR2 is overexpressed in GC, particularly diffuse-type GC, and is associated with poor prognostic outcomes. In recent years, there has been an increasing number of small molecule inhibitors and monoclonal antibodies targeting FGFR2 that have entered into clinical trials. Specifically for GC, these agents are currently being trialed in various phases as monotherapies or with standard-of-care treatments to make a clinically meaningful impact on what appears to be an important biological axis of GC. In this review, we outline the underlying biology of FGFR2, its putative role in GC, and the various FGFR2-targeted agents currently in clinical trials for gastric cancer patients as well as postulate some challenges in adopting these therapeutics for clinically meaningful benefit.
Assuntos
Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Neoplasias Gástricas , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/terapia , Humanos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Terapia de Alvo Molecular/métodos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologiaRESUMO
Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently recognised tumor type with indolent behaviour with characteristic imaging and histomolecular features. We describe the clinical, imaging, histo-molecular features of 15 cases diagnosed as low-grade glioma suggestive of PLNTY, over a period of 3 years. Immunohistochemistry (IHC) and fluorescence in situ hybridisation were used to assess molecular alterations. The tumors were seen predominantly in children (range 5-65 years). Most of the patients presented with history of seizures. Imaging revealed cortical-subcortical well demarcated solid-cystic tumor with intratumoral calcification. Histopathology revealed a low-grade tumor with oligodendroglia-Iike cells admixed with astrocytic cells immunopositive for CD34. BRAF p.V600E mutations and FGFR2 breakapart were observed in six cases each, while three showed FGFR3 breakapart. FGFR2 breakapart positive PLNTY were seen in children exclusively. The majority of cases were seizure free post-surgery, except two patients who succumbed to the illness. PLNTY, needs to be considered as a prime differential diagnosis in a solid-cystic tumor in a young patient with history of seizures. Characteristic clinical features, radiology, histomorphology with an IHC panel of OLIG2, GFAP and CD34 correlates with one of the MAPK alterations in PLNTY (BRAF p.V600E, FGFR2/3 gene rearrangement). In a resource limited setting, this limited panel may be sufficient for a correlative diagnosis.
Assuntos
Neoplasias Encefálicas , Neoplasias Neuroepiteliomatosas , Proteínas Proto-Oncogênicas B-raf , Humanos , Neoplasias Neuroepiteliomatosas/patologia , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/diagnóstico , Neoplasias Neuroepiteliomatosas/diagnóstico por imagem , Criança , Feminino , Masculino , Adolescente , Pré-Escolar , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/diagnóstico por imagem , Adulto , Proteínas Proto-Oncogênicas B-raf/genética , Pessoa de Meia-Idade , Mutação , Adulto Jovem , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Sistema de Sinalização das MAP Quinases , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Idoso , Hibridização in Situ Fluorescente , Imuno-Histoquímica , Antígenos CD34/análise , Diagnóstico Diferencial , Glioma/patologia , Glioma/diagnóstico , Glioma/genética , Glioma/diagnóstico por imagem , Fator de Transcrição 2 de Oligodendrócitos/genéticaRESUMO
We describe a case of a 47-year-old male patient with initially unresectable intrahepatic cholangiocarcinoma of the right liver lobe with tumor thrombi extending from the right bile duct to the common and left bile ducts. Conventional chemotherapy with gemcitabine and cisplatin for 19 months resulted in progressive disease. Subsequently, a comprehensive genome profile revealed fibroblast growth factor receptor 2 rearrangement, and hence, pemigatinib administration was initiated. After 6 months of pemigatinib therapy, significant shrinking of the tumor and disappearance of the tumor thrombi in the common and left bile duct were observed. Subsequently, the patient underwent conversion surgery, resulting in successful radical resection of the tumor. The patient has been disease-free for 7 months.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/cirurgia , Masculino , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/cirurgia , Pessoa de Meia-Idade , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Ductos Biliares Intra-Hepáticos/cirurgia , Hepatectomia/métodos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Antineoplásicos/uso terapêutico , Morfolinas , PirróisRESUMO
Background: Diagnostic classification of thyroid malignancy is primarily accomplished through examination of histomorphological features and may be substantiated and clarified by molecular data. Individual molecular drivers show relatively robust and specific associations with histological subtypes of thyroid malignancy, including BRAF sequence variants and kinase gene fusions in papillary thyroid carcinoma, predominantly RAS variants in follicular-patterned neoplasia, and additional "late" mutations affecting TERT promoter, TP53, and the PI3K/AKT/PTEN pathway in high-grade malignancies. Given the oncogenic role of FGFR, particularly FGFR1-3, the goal of this study was to explore the role of FGFR in thyroid carcinoma biology. Methods: We completed a multicenter retrospective observational study for thyroid carcinomas with pathogenic alterations in the FGFR gene family. We performed this study by querying the molecular data accumulated for thyroid carcinomas from each center. Results: Overall, 5030 sequenced thyroid malignancies were reviewed, yielding 17 tumors with FGFR alterations, including 11 where FGFR was the primary molecular driver and 6 where FGFR was a secondary pathogenic alteration, with a subset for which there was available clinical follow-up data. Of the 11 carcinomas with an FGFR driver, 9 were gene fusions involving FGFR2:VCL (4 tumors), TG::FGFR1 (3 tumors), FGFR2::CIT, and FGFR2::SHTN1, and the remaining 2 were driven by FGFR1 amplification. In the 6 tumors where a canonical driver of thyroid neoplasia was present (5 cases) or no clear primary driver was detected (1 case), sequencing detected secondary FGFR2 p.W290C, p.Y375C, and p.N549K, as well as FGFR1 p.N546K in the respective tyrosine kinase domains, some at subclonal variant allele frequencies. Conclusions: This study presents the first description of a collection of thyroid carcinomas grouped by primary driver alterations in FGFR, as well as a cohort of thyroid tumors with secondary alterations that potentially lead to tumor progression or resistance to targeted therapy. Given the availability of small molecular inhibitors targeting oncogenic FGFR, this study emphasizes the significant implications for patients from identification of FGFR alterations as they are currently under-recognized in the literature and, most importantly, have potential novel treatment options.
Assuntos
Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Estudos Retrospectivos , Masculino , Mutação , Feminino , Pessoa de Meia-Idade , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Adulto , Idoso , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologiaRESUMO
Fibroblast growth factor 7 (FGF7), also known as keratinocyte growth factor (KGF), is an important member of the FGF family that is mainly expressed by cells of mesenchymal origin while affecting specifically epithelial cells. Thus, FGF7 is widely expressed in diverse tissues, especially in urinary system, gastrointestinal tract (GI-tract), respiratory system, skin, and reproductive system. By interacting specifically with FGFR2-IIIb, FGF7 activates several downstream signal pathways, including Ras, PI3K-Akt, and PLCs. Previous studies of FGF7 mutants also have implicated its roles in various biological processes including development of essential organs and tissue homeostasis in adults. Moreover, more publications have reported that FGF7 and/or FGF7/FGFR2-IIIb-associated signaling pathway are involved in the progression of various heritable or acquired human diseases: heritable conditions like autosomal dominant polycystic kidney disease (ADPKD) and non-syndromic cleft lip and palate (NS CLP), where it promotes cyst formation and affects craniofacial development, respectively; acquired non-malignant diseases such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), mucositis, osteoarticular disorders, and metabolic diseases, where it influences inflammation, repair, and metabolic control; and tumorigenesis and malignant diseases, including benign prostatic hyperplasia (BPH), prostate cancer, gastric cancer, and ovarian cancer, where it enhances cell proliferation, invasion, and chemotherapy resistance. Targeting FGF7 pathways holds therapeutic potential for managing these conditions, underscoring the need for further research to explore its clinical applications. Having more insights into the function and underlying molecular mechanisms of FGF7 is warranted to facilitate the development of effective treatments in the future. Here, we discuss FGF7 genomic structure, signal pathway, expression pattern during embryonic development and in adult organs and mutants along with phenotypes, as well as associated diseases.
Assuntos
Fator 7 de Crescimento de Fibroblastos , Transdução de Sinais , Humanos , Fator 7 de Crescimento de Fibroblastos/genética , Fator 7 de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/genética , Animais , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismoRESUMO
PURPOSE: FGFR2 fusions occur in 10% to 15% of patients with intrahepatic cholangiocarcinoma (iCCA), potentially benefiting from FGFR inhibitors (FGFRi). We aimed to assess the feasibility of detecting FGFR2 fusions in plasma and explore plasma biomarkers for managing FGFRi treatment. EXPERIMENTAL DESIGN: We conducted a retrospective study in 18 patients with iCCA and known FGFR2 fusions previously identified in tissue samples from prior FGFRi treatment. Both tissue and synchronous plasma samples were analyzed using a custom hybrid capture gene panel with next-generation sequencing (VHIO-iCCA panel) and validated against commercial vendor results. Longitudinal plasma analysis during FGFRi was performed. Subsequently, we explored the correlation between plasma biomarkers, liver enzymes, tumor volume, and clinical outcomes. RESULTS: Sixteen patients (88.9%) were positive for FGFR2 fusion events in plasma. Remarkably, the analysis of plasma suggests that lower levels of ctDNA are linked to clinical benefits from targeted therapy and result in improved progression-free survival and overall survival. Higher concentrations of cell-free DNA before FGFRi treatment were linked to worse overall survival, correlating with impaired liver function and indicating compromised cell-free DNA removal by the liver. Additionally, increased ctDNA or the emergence of resistance mutations allowed earlier detection of disease progression compared with standard radiologic imaging methods. CONCLUSIONS: VHIO-iCCA demonstrated accurate detection of FGFR2 fusions in plasma. The integration of information from various plasma biomarkers holds the potential to predict clinical outcomes and identify treatment failure prior to radiologic progression, offering valuable guidance for the clinical management of patients with iCCA.
Assuntos
Neoplasias dos Ductos Biliares , Biomarcadores Tumorais , Colangiocarcinoma , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Humanos , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Colangiocarcinoma/sangue , Colangiocarcinoma/diagnóstico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Biópsia Líquida/métodos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/sangue , Neoplasias dos Ductos Biliares/mortalidade , Estudos Retrospectivos , Proteínas de Fusão Oncogênica/genética , Terapia de Alvo Molecular/métodos , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/sangue , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Adulto , Prognóstico , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
INTRODUCTION: Hypospadias is a common malformation of the genitourinary system and is thought with a complex interplay between genetics and environmental factors likely contributing to its pathogenesis. This study aimed to investigate the receptor gene expressions of sex hormones, FGFR2, FGF8 and BMP7 and DNA methylations in these genes as an epigenetic mark, which may play a role in the etiology of hypospadias. MATERIAL AND METHODS: The samples from the foreskin of 20 patients with hypospadias and 20 healthy children who underwent circumcision operations were collected. AR, ESR1, FGF8, FGFR2 and BMP7 gene expressions and DNA methylation rates of these genes were investigated in tissues. RESULTS: While ESR1, FGFR2 and BMP7 gene expressions were found to be significantly higher in the hypospadias group, AR gene expression was found to be lower. In the hypospadias group, DNA methylation rates were found to be significantly higher in the ESR1, FGF8 and FGFR2 genes, but lower in the AR gene (Table). DISCUSSION: Recent clinical studies suggest that epigenetic modifications may play a significant role in genital development, potentially contributing to the etiology of hypospadias. Our recent study demonstrated significant differences in foreskin AR, ESR1, and FGFR2 gene expression between patients with hypospadias and controls. To address this, the present study investigated DNA methylation levels of these same genes in hypospadias patients, hypothesizing that epigenetic modifications might be responsible for the observed gene expression changes. We again observed abnormalities in AR, ESR1, and FGFR2 gene expression in hypospadias patients. Furthermore, we found that DNA methylation patterns associated with these genes differed significantly between hypospadias and control groups. CONCLUSIONS: Our study demonstrates significant alterations in DNA methylation of sex hormone receptor genes (ESR1 and AR), FGFR2, and FGF8, which correlate with abnormal expression of these genes in hypospadias cases. These findings suggest a potential role for epigenetic modifications in hypospadias etiology.
Assuntos
Metilação de DNA , Epigênese Genética , Receptor alfa de Estrogênio , Hipospadia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Humanos , Masculino , Hipospadia/genética , Hipospadia/etiologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor alfa de Estrogênio/genética , Lactente , Pré-Escolar , Fator 8 de Crescimento de Fibroblasto/genética , Fator 8 de Crescimento de Fibroblasto/metabolismo , Receptores Androgênicos/genética , Estudos de Casos e Controles , Criança , Proteína Morfogenética Óssea 7RESUMO
BACKGROUND: The cause of duodenal atresia (DA) is not known. Tandler's "solid cord" hypothesis conflicts with current biological evidence. In humans, a genetic aetiology is supported by the association with Trisomy 21. Interruption of Fgf10 is the strongest genetic link to DA in mice, demonstrating an increased incidence and severity as embryos mature. This project aimed to develop an organoid model to facilitate ex vivo DA research on the FGF10/FGFR2b signalling pathway. We hypothesised that DA morphology represents an evolving spectrum of disease and that Fgf10 knockout organoids would vary in growth pattern compared to wild-type. METHODS: Organoids were cultured from the duodenum of E12.5 Fgf10 knockout, heterozygous and wild-type embryos, using an air-liquid interface with Growth Factor reduced Matrigel. Organoids were photographed every 48 h to observe growth. Organoids were isolated and fixed after 14 days, then stained with DAPI, KI-67, and cytokeratin to demonstrate proliferation and differentiation. RESULTS: Wild-type duodenum developed into crypt-forming organoids. Fgf10 heterozygous duodenum failed to progress beyond the development stage of spheroids. Fgf10 knockout duodenum failed to demonstrate any growth. Wholemount staining showed the greatest cell proliferation and differentiation in wild-type tissue. CONCLUSION: This research presents a novel concept for the growth of embryonic gastrointestinal tissue to inform normal biology. The small sample numbers and restricted culture duration limit longer-term growth analysis. While this model serves as a potential ex vivo setting for future research, that research should consider organoid models with greater standardisation and other gastrointestinal regions. LEVEL OF EVIDENCE: Animal/laboratory study.
Assuntos
Duodeno , Fator 10 de Crescimento de Fibroblastos , Atresia Intestinal , Camundongos Knockout , Organoides , Atresia Intestinal/embriologia , Animais , Fator 10 de Crescimento de Fibroblastos/genética , Camundongos , Duodeno/embriologia , Duodeno/anormalidades , Técnicas de Cultura de Órgãos/métodos , Obstrução Duodenal/embriologia , Obstrução Duodenal/genética , Proliferação de Células , Transdução de Sinais , Diferenciação Celular , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
Patients with cancer of unknown primary (CUP) carry the double burden of an aggressive disease and reduced access to therapies. Experimental models are pivotal for CUP biology investigation and drug testing. We derived two CUP cell lines (CUP#55 and #96) and corresponding patient-derived xenografts (PDXs), from ascites tumor cells. CUP cell lines and PDXs underwent histological, immune-phenotypical, molecular, and genomic characterization confirming the features of the original tumor. The tissue-of-origin prediction was obtained from the tumor microRNA expression profile and confirmed by single-cell transcriptomics. Genomic testing and fluorescence in situ hybridization analysis identified FGFR2 gene amplification in both models, in the form of homogeneously staining region (HSR) in CUP#55 and double minutes in CUP#96. FGFR2 was recognized as the main oncogenic driver and therapeutic target. FGFR2-targeting drug BGJ398 (infigratinib) in combination with the MEK inhibitor trametinib proved to be synergic and exceptionally active, both in vitro and in vivo. The effects of the combined treatment by single-cell gene expression analysis revealed a remarkable plasticity of tumor cells and the greater sensitivity of cells with epithelial phenotype. This study brings personalized therapy closer to CUP patients and provides the rationale for FGFR2 and MEK targeting in metastatic tumors with FGFR2 pathway activation.
Assuntos
Neoplasias Primárias Desconhecidas , Inibidores de Proteínas Quinases , Piridonas , Pirimidinonas , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Animais , Feminino , Humanos , Camundongos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Amplificação de Genes , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Primárias Desconhecidas/tratamento farmacológico , Neoplasias Primárias Desconhecidas/genética , Neoplasias Primárias Desconhecidas/patologia , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/farmacologia , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirimidinonas/farmacologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Over recent years, there has been a notable rise in the incidence of intrahepatic cholangiocarcinoma (iCCA), which presents a significant challenge in treatment due to its complex disease characteristics and prognosis. Notably, the identification of fibroblast growth factor receptor 2 (FGFR2) fusion/rearrangement, a potential oncogenic driver primarily observed in iCCA, raises questions about its impact on the prognostic outcomes of patients undergoing surgical intervention or other therapeutic approaches. METHODS: A comprehensive search from inception to July 2023 was conducted across PubMed, Embase, Web of Science, and the Cochrane Library databases. The objective was to identify relevant publications comparing the prognosis of FGFR2 alterations and no FGFR2 alterations groups among patients with iCCA undergoing surgical resection or other systemic therapies. The primary outcome indicators, specifically Overall Survival (OS) and Disease-Free Survival (DFS), were estimated using Hazard Ratios (HRs) with 95% confidence intervals (CIs), and statistical significance was defined as p < .05. Study quality was assessed using the Newcastle-Ottawa Quality Assessment Scale. Statistical analyses were performed using Review Manager 5.4 software and Stata, version 12.0. RESULTS: Six studies, involving 1314 patients (FGFR2 alterations group n = 173 and no FGFR2 alterations group n = 1141), were included in the meta-analysis. The analysis revealed that the FGFR2 alterations group exhibited a significantly better OS prognosis compared to the no FGFR2 alterations group, with a fixed-effects combined effect size HR = 1.31, 95%CI = 1.001-1.715, p = .049. Furthermore, meta-regression and subgroup analysis showed that the length of the follow-up period did not introduce heterogeneity into the results. This finding indicates the stability and reliability of the study outcomes. CONCLUSION: The current study provides compelling evidence that FGFR2 alterations are frequently associated with improved survival outcomes for patients with iCCA undergoing surgical resection or other systemic treatments. Additionally, the study suggests that FGFR2 holds promise as a safe and dependable therapeutic target for managing metastatic, locally advanced or unresectable iCCA. This study offers a novel perspective in the realm of targeted therapy for iCCA, presenting a new and innovative approach to its treatment.