Search

Human exposure to organotin is common but little is known about the adverse pregnancy outcomes. This study aimed to explore the association between organotin exposure and the risk of non-syndromic cleft lip with or without cleft palate (NSCL/P) and to explore the underlying mechanism. Placental samples (109 NSCL/P cases and 128 controls) were analyzed for 8 organotin concentrations, and subsequent animal experiments were conducted by administering tributyltin (TBT) during critical developmental periods. DNA methylation BeadChip analysis (12 NSCL/P and 12 controls), bisulfite Sequencing analysis (3 NSCL/P and 3 controls mice), and RNA sequencing were performed to explore epigenetic mechanisms. Logistic regression, LASSO regression, support vector machine, random forest, and mediation effect analysis were utilized to identify key genes related to TBT and NSCL/P. Only tributyltin met the detection criteria for further analysis among 8 compounds. The median levels of TBT in cases (8.93 ng/g) were statistically significantly higher than those in controls (5.33 ng/g). Excessive TBT exposure in maternal placenta was associated with an increased risk of NSCL/P (OR = 6.44, 95 % CI, 2.91-14.25) in humans, showing a dose-response relationship (p for trend <0.05). 288 differentially methylated CpG sites in 129 genes were identified between cases and controls. Tributyltin was associated with FGFR2 and SCD hypomethylation, which were identified as potential key genes associated with NSCL/P. Mediation analysis suggested that DNA methylation of FGFR2 and SCD may mediate the impact of TBT on NSCL/P occurrence. TBT exposure during the critical period in mice (GD8.5-GD15.5) can induce progeny NSCL/P. Altered FGFR2 and SCD hypomethylation and gene expression observed in response to TBT exposure in fetal mice. Excessive TBT exposure was associated with increased risks of human NSCL/P. TBT exposure can induce NSCL/P in fetal mice. FGFR2 and SCD were implicated in NSCL/P pathogenesis, potentially mediated by DNA methylation alterations., Competing Interests: Declaration of competing interest All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Crouzon syndrome is a congenital craniofacial disorder caused by mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2). It is characterized by the premature fusion of cranial sutures, leading to a brachycephalic head shape, and midfacial hypoplasia. The aim of this study was to investigate the effect of the FGFR2 mutation on the microarchitecture of cranial bones at different stages of postnatal skull development, using the FGFR2 C342Y mouse model. Apart from craniosynostosis, this model shows cranial bone abnormalities. High-resolution synchrotron microtomography images of the frontal and parietal bone were acquired for both FGFR2 C342Y/+ (Crouzon, heterozygous mutant) and FGFR2 +/+ (control, wild-type) mice at five ages (postnatal days 1, 3, 7, 14 and 21, n = 6 each). Morphometric measurements were determined for cortical bone porosity: osteocyte lacunae and canals. General linear model to assess the effect of age, anatomical location and genotype was carried out for each morphometric measurement. Histological analysis was performed to validate the findings. In both groups (Crouzon and wild-type), statistical difference in bone volume fraction, average canal volume, lacunar number density, lacunar volume density and canal volume density was found at most age points, with the frontal bone generally showing higher porosity and fewer lacunae. Frontal bone showed differences between the Crouzon and wild-type groups in terms of lacunar morphometry (average lacunar volume, lacunar number density and lacunar volume density) with larger, less dense lacunae around the postnatal age of P7-P14. Histological analysis of bone showed marked differences in frontal bone only. These findings provide a better understanding of the pathogenesis of Crouzon syndrome and will contribute to computational models that predict postoperative changes with the aim to improve surgical outcome., (© 2024 The Author(s). Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)

NRAS Q61 mutations are driver genetic alterations associated with common melanocytic nevi. Herein, we describe a case of NRAS-mutant melanocytic tumor with a blue nevus-like morphology. A 71-year-old Japanese man presented with a 4.6-mm nodule on his back. Histopathological examination revealed a dense distribution of spindle-shaped melanocytes in the upper dermis and a sparse distribution of dendritic melanocytes in the mid-dermis. The vertical periadnexal extension reached the deep dermis at the center of the tumor. A small junctional component, hyperpigmentation, sclerotic stroma, mild nuclear atypia, and a few mitotic figures were observed. Immunohistochemical examination revealed no PRAME expression and preserved p16 expression. Diffuse RASQ61R immunoreactivity was observed in these tumor cells. Nuclear β-catenin expression was not observed. Targeted RNA sequencing revealed two mutations, NRAS c.182A>G (Q61R) and FGFR2 c.-157A>G, but no other pathogenic alterations such as BRAF, GNAQ, GNA11, CTNNB1, PRKAR1A, or IDH1 mutations or kinase gene fusions. The histopathology fits that of compound-type blue nevus, which is called "Kamino nevus"; however, this tumor was genetically considered to be on the spectrum of conventional acquired melanocytic nevi but not on that of blue nevi. Morphologically, NRAS-driven melanocytic nevi resemble blue nevi without IDH1 R132C coexistence., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This article is based on my talk at the meeting "3rd Advances in Craniosynostosis: Basic Science to Clinical Practice", held at University College, London, on 25 August 2023. It describes my contribution, together with that of my research team and external collaborators, to the field of craniofacial development. This began with my PhD research on the effects of excess vitamin A in rat embryos, which led to a study of normal as well as abnormal formation of the cranial neural tube. Many techniques for analysing morphogenetic change became available to me over the years: whole embryo culture, scanning and transmission electron microscopy, cell division analysis, immunohistochemistry and biochemical analysis of the extracellular matrix. The molecular revolution of the 1980s, and key collaborations with international research teams, enabled functional interpretation of some of the earlier morphological observations and required a change of experimental species to the mouse. Interactions between the molecular and experimental analysis of craniofacial morphogenesis in my laboratory with specialists in molecular genetics and clinicians brought my research journey near to my original aim: to contribute to a better understanding of the causes of human congenital anomalies., (© 2024 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)

Background & Objective: Bladder carcinoma ranks second in prevalence among males in Egypt. As a family of tyrosine kinases, fibroblast growth factor receptor (FGFR) dysregulation has been linked to some malignancies in humans. The aim of this study is to analyze the clinicopathological data of patients while investigating FGFR2 and FGFR3 immunohistochemical expression in invasive urothelial bladder carcinoma., Methods: This retrospective cross-sectional study included 60 invasive urothelial carcinoma (UC) cases in the Pathology department, Faculty of Medicine, Menoufia University, from 2009 to 2020. All biopsies were stained for FGFR2 and FGFR3 antibodies. Complete clinical data were available for 44 patients treated and followed in clinical oncology and nuclear medicine departments., Results: Advanced stage and high grade are significantly correlated with FGFR2 positivity ( P =0.048 and 0.044, respectively). Cases presented with Perineural invasion showed a higher percentage of FGFR2 ( P =0.023). There is a significant indirect linear correlation between FGFR3 expression and lymph node positivity (r= -0.265, P =0.041)., Conclusion: A high FGFR2 expression could be associated with poor prognostic parameters, while high FGFR3 expression would be associated with good prognostic parameters. These findings might highlight the importance of FGFR-targeted therapy as a FGFR2 antagonist and FGFR3 agonist for the treatment of urothelial carcinoma patients., Competing Interests: The authors declare that they have no potential conflicts of interest to disclose., (© 2024.)

Fibroblast growth factor receptor 2 (FGFR2) has been associated with breast cancer. We performed in silico analyses to investigate the FGFR2 mRNA expression and splice variants associated with breast cancer subtypes. Online databases, including cBioPortal and TCGA SpliceSeq, were used to examine the association between the FGFR2 expression and splice variants with breast cancer subtypes. A higher FGFR2 mRNA was significantly associated with luminal, oestrogen receptor (ER)-positive breast cancers, and invasive lobular carcinomas, whereas a lower FGFR2 was associated with human epidermal growth factor receptor 2 (HER2)-positive breast cancer and invasive ductal carcinomas. The epithelial alternatively spliced FGFR2 IIIb isoform was significantly enriched in ER+ breast cancer, while the mesenchymal FGFR2 IIIc isoform was significantly prevalent in HER2+ cancer. Increased levels of FGFR2 and IIIb splice isoforms are associated with less aggressive breast cancer phenotypes, while decreased levels of FGFR2 and increased IIIc splice isoform are associated with more aggressive phenotypes.

Targeted treatment of advanced or metastatic urothelial carcinomas (UCs) requires the identification of druggable mutations. This study describes the development of a 3' Rapid Amplification of cDNA Ends (3' RACE)-based targeted RNA sequencing panel which accounts for the status of all genes relevant to UC treatment, namely, FGFR1-4 , KRAS , NRAS , BRAF , ERBB2 ( HER2 ), CD274 ( PD-L1 ) and PIK3CA . FGFR2/3 -activating point mutations or fusions were found in 54/233 (23.2%) tumors. FGFR3 rearrangements were identified in 11 patients, with eight of them being undetectable by commonly used PCR kits. In addition, one tumor contained a high-copy FGFR2 gene amplification accompanied by strong overexpression of the gene. Mutations in RAS/RAF genes were present in 30/233 (12.9%) UCs and were mutually exclusive with alterations affecting FGFR2/3 genes. On the contrary, activating events in the HER2 oncogene (point mutations and overexpression), as well as PIK3CA mutations, which were relatively common, occurred with similar frequencies in RAS/RAF - or FGFR2/3 -positive vs. negative samples. High PD-L1 mRNA expression was associated with advanced disease stage and was not observed in tumors with increased HER2 mRNA expression or in UCs with evidence for FGFR2/3 activation. Three of the studied carcinomas had high-level microsatellite instability (MSI). Overall, more than half of the UCs had potentially druggable genetic alterations. The proposed NGS panel permits comprehensive and cost-efficient analysis of UC-specific molecular targets and may be considered in clinical routine.

This report presents a rare case of a 45-year-old man diagnosed with a primary hepatic alpha-fetoprotein-producing neuroendocrine neoplasm, a condition rarely reported in the literature. The patient presented with initial symptoms of back and epigastric pain, after which multiple liver lesions were discovered on contrast-enhanced computed tomography, suggesting intrahepatic cholangiocarcinoma. Histopathological and immunohistochemical analyses confirmed the diagnosis of alpha-fetoprotein-producing neuroendocrine neoplasm that was further supported by genetic testing, which revealed FGFR2 and TP53 mutations commonly encountered in intrahepatic cholangiocarcinoma. Despite receiving various chemotherapeutic regimens, the patient exhibited a progressive disease. This case underscores the importance of accurate differential diagnosis from hepatocellular carcinoma and intrahepatic cholangiocarcinoma due to differences in treatment approaches and prognoses and highlights the necessity for increased awareness of AFP-producing primary hepatic neuroendocrine neoplasms among clinicians and pathologists. It emphasizes the significance of comprehensive histopathological evaluation, immunohistochemical profiling, and genetic analysis for precise diagnosis and tailored therapeutic strategies. Further research is warranted to elucidate the molecular mechanisms underlying this rare liver tumor subtype and develop targeted treatments., (© 2024. The Author(s).)

Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study. Based on the safety, pharmacokinetic, and pharmacodynamic profiles observed in this study, the recommended dose of 140 mg once daily was selected for the expansion part (Part 2), a multicenter expansion of the dose-finding study restricted to patients with tumors harboring FGFR gene alterations. Safety and preliminary efficacy were assessed in Part 2. Pharmacodynamic pharmacogenomic markers (serum phosphate, FGF23, and 1,25-(OH) 2 -vitamin D, circulating tumor DNA) and pharmacokinetic profiles were also evaluated. A total of 16 patients were enrolled in Part 2, six with cholangiocarcinoma and 10 with gastric cancer. The most common treatment-emergent adverse events were hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, and paronychia. Five partial responses (83.3%) in cholangiocarcinoma patients and one partial response (11.1%) in gastric cancer patients were observed; median progression-free survival was 8.26 months (95% confidence interval [CI] 3.84, not evaluable [NE]) and 3.25 months (95% CI 0.95, 4.86), and overall survival was 22.49 months (95% CI 6.37, NE) and 4.27 months (95% CI 2.23, 7.95), respectively, in the two groups. In conclusion, Tasurgratinib 140 mg has a tolerable safety profile with good clinical efficacy in patients with cholangiocarcinoma harboring FGFR2 gene rearrangements., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

A 53 year old female presented with a six-year history of right-sided slow deterioration in hearing and a feeling of pressure in the right ear. The patient had not experienced any pain but reported some paresthesia of the right half of the tongue, whereas no further other cranial nerve deficits were evident. The otoscopy was unremarkable as well as the rest of the clinical ENT examination except for a slight asymptomatic swelling of the right cheek. Imaging findings showed an expansive tumor infiltrating and destroying the right lateral skull base. The tumor was partially composed of cystic/regressive lesions with high contrast media uptake. The tumor had high-signal intensity with water-sensitive sequences (T2w) and was hypointense on T1w images. We performed a tumor resection via a transparotideal-infratemporal approach. Histologically, the tumor was composed of granular variably calcified chondroid matrix with extensive regressive changes and granulation-like tissue reaction associated with calcinosis and crystal deposition. Molecular analysis of the tumor via the TruSight- RNA-Fusion panel detected a fusion involving FN1::FGFR2, consistent with "calcified chondroid mesenchymal neoplasm" (CCMN), a rare tumor entity recently defined by Liu et al 2021. In regular follow-up care no residual tumor has been detected in imaging studies (MRI and CT) within 2 years and 4 months. The biology and consequently the radio sensitivity cannot be defined precisely since long term results are missing due to the first description of this entity in 2021. As a consequence, surgical resection is recommended as the treatment of choice. Thorough clinical and radiological follow-up is mandatory as local recurrences are to be expected due to the infiltrative behavior. In case of a loco regional recurrence the fusion with FGFR2 may represent a therapeutic option for a targeted therapy on molecular level., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

Our understanding of neoadjuvant treatment with microtubule inhibitors (MTIs) for triple negative breast cancer (TNBC) remains limited. To advance our understanding of the role of breast cancer driver genes' mutational status with pathological complete response (pCR; ypT0/isypN0) prediction and to identify distinct gene sets for MTIs like eribulin and paclitaxel, we carried out targeted genomic (n = 50) and whole transcriptomic profiling (n = 64) of TNBC tumor samples from the Japan Breast Cancer Research Group 22 (JBCRG-22) clinical trial. Lower PIK3CA, PTEN, and HRAS mutations were found in homologous recombination deficiency (HRD)-high (HRD score ≥ 42) tumors with higher pCR rates. When HRD-high tumors were stratified by tumor BRCA mutation status, the pCR rates in BRCA2-mutated tumors were higher (83% vs. 36%). Transcriptomic profiling of TP53-positive tumors identified downregulation of FGFR2 (false discovery rate p value = 2.07e-7), which was also the only common gene between HRD-high and -low tumors with pCR/quasi-pCR treated with paclitaxel and eribulin combined with carboplatin, respectively. Differential enrichment analysis of the HRD-high group posttreatment tumors revealed significant correlation (p = 0.006) of the glycan degradation pathway. FGFR2 expression and the differentially enriched pathways play a role in the response and resistance to MTIs containing carboplatin treatment in TNBC patients., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

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., Competing Interests: Declaration of interests F.G. received personal fees from AstraZeneca and honoraria for advisory board participation from Eli-Lilly. G.A.C. is a member of the Editorial Board of Molecular Therapy., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Biliary tract cancer, the second most common type of liver cancer, remains a therapeutic challenge due to its late diagnosis and poor prognosis. In recent years, it has become evident that classical chemotherapy might not be the optimal treatment for patients with biliary tract cancer, especially after failure of first-line therapy. Finding new treatment options and strategies to improve the survival of these patients is therefore crucial. With the rise and increasing availability of genetic testing in patients with tumor, novel treatment approaches targeting specific genetic alterations have recently been proposed and have demonstrated their safety and efficacy in numerous clinical trials. In this review, we will first consider chemotherapy options and the new possibility of combining chemotherapy with immune checkpoint inhibitors in first-line treatment. We will then provide an overview of genomic alterations and their potential for targeted therapy especially in second-line therapy. In addition to the most common alterations such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, fibroblast growth factor receptor 2 (FGFR2) fusions, and alterations, we will also discuss less frequently encountered alterations such as BRAF V600E mutation and neurotrophic tyrosine kinase receptor gene (NTRK) fusion. We highlight the importance of molecular profiling in guiding therapeutic decisions and emphasize the need for continued research to optimize and expand targeted treatment strategies for this aggressive malignancy., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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 (Fgfr2 C361Y/+ ) 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). Fgfr2 C361Y/+ 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 Fgfr2 C361Y/+ 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. Fgfr2 C361Y/+ mice replicate CS phenotypes-craniosynostosis and midface anomalies. Mutant mice show diverse behavioral abnormalities, impacting learning and memory. Fgfr2 C361Y/+ mice offer a novel model for cranial suture studies and therapeutic exploration., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (© 2024. The Author(s), under exclusive licence to The Japan Society of Brain Tumor Pathology.)

Aberrant activation of fibroblast growth factor receptors (FGFRs) contributes to the development and progression of multiple types of cancer. Although many FGFR inhibitors have been approved by the FDA, their long-term therapeutic efficacy is hampered by acquired resistance to gatekeeper mutations and low subtype selectivity. FGFR2 has been found to be frequently amplified or mutated in many tumors. In this study, we designed several PROTACs with different E3 ligands based on LY2874455. By screening the length of the linker and the binding site in various degraders, we obtained a novel and highly efficient FGFR2-selective degrader 28e (DC 50  = 0.645 nM, DC max  = 86 %). Compound 28e selectively degraded FGFR2 and essentially avoided degradation of FGFR1,3,4 isoforms (DC 50  > 300 nM). Compound 28e significantly inhibited the proliferation of FGFR2-overexpressing cell lines, including KATOIII, SNU16, and AN3CA (IC 50  = 0.794 nM/0.207 nM/4.626 nM), comparable to parental inhibitors. At the same time, the preferred compound showed superiority over the parental inhibitor in kinase inhibitory activity against the gatekeeper mutant isoform FGFR2 V564F (IC 50  = 0.121 nM). In summary, we identified 28e as a novel selective degrader of FGFR2 with high potency and high potential to overcome resistance to gatekeeper mutation. The discovery of 28e provides new evidence for the strategy of pan-inhibitor-based development of selective degrading agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Pemigatinib demonstrated efficacy in fibroblast growth factor receptor (FGFR)-altered cholangiocarcinoma (CCA) in the FIGHT-202 trial. However, limited real-world evidence exists on treatment patterns and outcomes in this setting., Patients and Methods: Patient characteristics, treatment patterns, and outcomes of US adults who received pemigatinib for unresectable, locally advanced or metastatic CCA were collected via retrospective physician-abstracted chart review. Results were summarized using descriptive statistics., Results: Data from 120 patients (49.2% male; 55.0% White; 19.2% Hispanic; median age at initial pemigatinib prescription, 64.5 years) were collected from 18 physicians/practices. At the time of prescribing, 90.0% of patients had metastatic disease. FGFR2 testing was completed for 92.5% of patients; of those, all but one (result unknown) tested positive, and 95.5% were tested using next-generation sequencing. Pemigatinib was prescribed as second- and third-line therapy among 94.2% and 5.8% of patients, respectively. The most common starting dosage was 13.5 mg daily for 14 days of 21-day cycles (87.5% of patients). Among 60 patients (50.0% of the full cohort) who discontinued pemigatinib during the 6.5-month median study follow-up period, 68.3% discontinued due to disease progression. The median real-world progression-free survival (rwPFS) from the date of pemigatinib initiation was 7.4 months (95% CI: 6.4-8.6), and the real-world overall response rate (rwORR) was 59.2% (95% CI: 50.0%-68.4%)., Conclusion: This study complements the FIGHT-202 clinical trial by assessing the use of pemigatinib among a diverse population of patients with CCA under real-world conditions. Findings support the clinical benefit of pemigatinib demonstrated in FIGHT-202., (© The Author(s) 2024. Published by Oxford University Press.)

Intraductal tubulopapillary neoplasms (ITPNs) are rare pancreatic tumors with distinct histological and molecular features. Distinction of ITPN from other pancreatic neoplasms is crucial given the known favorable prognosis and the high frequency and diversity of potentially targetable fusions in ITPN. While the histological features of ITPN are well documented, there are few reports on the cytological features, and molecular characterization of ITPN. The authors reported three cases diagnosed in their laboratory between 2016 and 2021. Clinical data, cytomorphological and histological features, with immunophenotypic and molecular characterizations of these cases are described and compared with those reported in the literature. All 3 cases were diagnosed as ITPN based on the microscopic presence of intraductal nodules composed of tightly packed small tubular glands lined by cuboidal cells lacking apparent mucin. On molecular profiling KRAS and TP53 variants were found in Case 1, FGFR2-INA fusion in Case 2, and STARD3NL-BRAF fusion was detected in Case 3. Immunohistochemistry (IHC) revealed that the neoplastic cells in Case 1 were MUC2 positive and MUC6 negative, but in Cases 2 and 3, were negative for MUC2 and positive for MUC6. These results demonstrate the immunophenotypic and molecular variabilities of histologically similar pancreatic neoplasms. The absence of alterations characteristic of more common pancreatic neoplasms should prompt the consideration of fusion studies in morphologically relevant cases. The combination of morphological, IHC, and molecular analyses is important for reliable identification of ITPN given its potential clinical management implications., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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.

Increasing evidence highlights that fibroblast growth factor receptor 2 (FGFR2) fusion/rearrangement shows important therapeutic value for patients with intrahepatic cholangiocarcinoma (ICC). This study aims to explore the association of FGFR2 status with the prognosis and immune cell infiltration profiles of patients with ICC. A total of 226 ICC tissue samples from patients who received surgery at the Department of Liver Surgery at Zhongshan Hospital, Fudan University, were collected retrospectively and assigned to a primary cohort (n = 152) and validation cohort (n = 74) group. Fluorescence in situ hybridization was performed to determine FGFR2 status. Multiplex immunofluorescence (mIF) staining and immunohistochemistry were performed to identify immune cells. Thirty-two (14.2%) ICC tissues presented with FGFR2 fusion/rearrangement. FGFR2 fusion/rearrangement was associated with low levels of carcinoembryonic antigen (CEA, P = .026) and gamma glutamyl transferase (γ-GGT, P = .003), low TNM (P = .012), CNLC (P = .008) staging as well as low tumor cell differentiation (P = .016). Multivariate COX regression analyses revealed that FGFR2 fusion/rearrangement was an independent protective factor for both overall survival (OS) and relapse-free survival in patients with ICC. Furthermore, correlation analysis revealed that an FGFR2 fusion/rearrangement was associated with low levels of Tregs and N2 neutrophils and high levels of N1 neutrophils infiltrating into tumors but not with CD8+ T-cell or macrophage tumor infiltration. FGFR2 fusion/rearrangement may exert a profound impact on the prognosis of ICC patients and reprogram the tumor microenvironment to be an immune-activated state. FGFR2 status may be used for ICC prognostic stratification and as an immunotherapeutic target in patients with ICC., (© The Author(s) 2024. Published by Oxford University Press.)

Cutaneous squamous cell carcinoma (cSCC) is a common and increasingly prevalent form of skin cancer, posing significant health challenges. Understanding the molecular mechanisms involved in cSCC progression is crucial for developing effective treatments. The primary aim of this research was to evaluate the activation of NOTCH1 and FGFR2 oncogenes in inducing skin cancer in FVB/N mice through a stepwise chemical process. Forty female FVB/N mice, aged four weeks, were randomly divided into a control group (n = 8) and two experimental groups (group A: n = 16, group B: n = 16). This study involved subjecting the groups to a two-stage carcinogenesis procedure. This included an initial application of 97.4 nmol DMBA on shaved skin on their backs, followed by applications of 32.4 nmol TPA after thirteen weeks for group A and after twenty weeks for group B. The control group did not receive any treatment. Their skin conditions were monitored weekly to detect tumor development. After the experiment, the animals were euthanized for further tissue sampling. The examination of skin lesions in the experimental groups showed a correlation with tumor progression, ranging from dysplasia to carcinoma. Tumor samples were assessed both histologically and immunohistochemically. Notably, FGFR2 expression was higher in benign, precancerous, and malignant tumors compared to normal tissue. NOTCH1 expression was only elevated in benign tumors compared to normal tissue. This study demonstrates a clear correlation of FGFR2 expression and the progression of cutaneous neoplasms, while NOTCH 1 expression is inversely correlated in FVB/N mice. This suggests an early involvement of these oncogenes in the development of skin tumors.

Background: The diagnosis of glioma has advanced since the release of the WHO 2021 classification with more molecular alterations involved in the integrated diagnostic pathways. Our study aimed to present our experience with the clinical features and management of astrocytoma, IDH mutant based on the latest WHO classification., Methods: Patients diagnosed with astrocytoma, IDH-mutant based on the WHO 5th edition classification of CNS tumors at our center from January 2009 to January 2022 were included. Patients were divided into WHO 2-3 grade group and WHO 4 grade group. Integrate diagnoses were retrospectively confirmed according to WHO 2016 and 2021 classification. Clinical and MRI characteristics were reviewed, and survival analysis was performed., Results: A total of 60 patients were enrolled. 21.67% (13/60) of all patients changed tumor grade from WHO 4th edition classification to WHO 5th edition. Of these, 21.43% (6/28) of grade II astrocytoma and 58.33% (7/12) of grade III astrocytoma according to WHO 4th edition classification changed to grade 4 according to WHO 5th edition classification. Sex (p = 0.042), recurrent glioma (p = 0.006), and Ki-67 index (p < 0.001) of pathological examination were statistically different in the WHO grade 2-3 group (n = 27) and WHO grade 4 group (n = 33). CDK6 (p = 0.004), FGFR2 (p = 0.003), and MYC (p = 0.004) alterations showed an enrichment in the WHO grade 4 group. Patients with higher grade showed shorter mOS (mOS = 75.9 m, 53.6 m, 26.4 m for grade 2, 3, and 4, respectively, p = 0.01)., Conclusions: Patients diagnosed as WHO grade 4 according to the 5th edition WHO classification based on molecular alterations are more likely to have poorer prognosis. Therefore, treatment should be tailored to their individual needs. Further research is needed for the management of IDH-mutant astrocytoma is needed in the future., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Whole salivary gland generation and transplantation offer potential therapies for salivary gland dysfunction. However, the specific lineage required to engineer complete salivary glands has remained elusive. In this study, we identify the Foxa2 lineage as a critical lineage for salivary gland development through conditional blastocyst complementation (CBC). Foxa2 lineage marking begins at the boundary between the endodermal and ectodermal regions of the oral epithelium before the formation of the primordial salivary gland, thereby labeling the entire gland. Ablation of Fgfr2 within the Foxa2 lineage in mice leads to salivary gland agenesis. We reversed this phenotype by injecting donor pluripotent stem cells into the mouse blastocysts, resulting in mice that survived to adulthood with salivary glands of normal size, comparable to those of their littermate controls. These findings demonstrate that CBC-based salivary gland regeneration serves as a foundational experimental approach for future advanced cell-based therapies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Biliary tract cancers (BTCs) are rare and aggressive malignancies with an increasing incidence and poor prognosis. The standard systemic treatment for BTCs has evolved to include immune checkpoint inhibitors associated with gemcitabine-cisplatin as first-line therapies. However, survival rates remain low, highlighting the critical need for personalized treatment strategies based on molecular profiling. Currently, significant advancements have been made in the molecular characterization of BTCs, where genetic alterations, such as IDH1 mutations and FGFR2 fusions, provide targets for therapy. Molecular profiling is crucial early in the management process to identify potential candidates for clinical trials and guide treatment strategy. The integration of these molecular insights into clinical practice has allowed for the development of targeted therapies, although many of them are still in the phase 2 trial stage without definitive survival benefits demonstrated in phase 3 trials. This integration of comprehensive molecular profile insights with traditional treatment approaches offers a new horizon in the personalized medicine landscape for BTCs, with the aim of significantly improving patient outcomes through precision oncology.

We report the novel clinical presentation of a primary brain neoplasm in a 30-year-old man with a mass-like area in the anteromedial temporal lobe. Histopathological analysis revealed a low-grade neuroepithelial tumor with cytologically abnormal neurons and atypical glial cells within the cerebral cortex. Molecular analysis showed a previously undescribed FGFR2::DLG5 rearrangement. We discuss the clinical significance and molecular implications of this fusion event, shedding light on its potential impact on tumor development and patient prognosis. Additionally, an extensive review places the finding in this case in the context of protein fusions in brain tumors in general and highlights their diverse manifestations, underlying molecular mechanisms, and therapeutic implications., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Fibroblast growth factor receptor 2 (FGFR2) represents an appealing therapeutic target for multiple cancers, yet no selective FGFR2 inhibitors have been approved for clinical use to date. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors. The representative compound LHQ490 potently inhibited FGFR2 kinase activity with an IC 50 of 5.2 nM, and was >61-, >34-, and >293-fold selective against FGFR1, FGFR3, and FGFR4, respectively. LHQ490 also exhibited high selectivity in a panel of 416 kinases. Cell-based studies revealed that LHQ490 efficiently suppressed the proliferation of BaF3-FGFR2 cells with an IC 50 value of 1.4 nM, and displayed >70- and >714-fold selectivity against BaF3-FGFR1 and the parental BaF3 cells, respectively. More importantly, LHQ490 potently suppressed the FGFR2 signaling pathways, selectively inhibited FGFR2-driven cancer cell proliferation, and induced apoptosis of FGFR2-driven cancer cells. Taken together, this study provides a potent and highly selective FGFR2 inhibitor for further development of FGFR2-targeted therapeutic agents., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Genetic alterations including fusions in fibroblast growth factor receptor 2 (FGFR2) are detected in 10-20% of intrahepatic cholangiocarcinoma (iCCA), and FGFR2 inhibitors are effective for the treatment of iCCA. We examined a prevalence of FGFR2 genetic alterations and their clinicopathological significance in combined hepatocellular-cholangiocarcinoma (cHCC-CCA). FGFR2 expression, which is a surrogate marker for FGFR2 genetic alterations, was immunohistochemically assessed in the liver sections from 75 patients with cHCC-CCA, 35 with small duct-type iCCA, 30 with large duct-type iCCA, and 35 with hepatocellular carcinoma (HCC). FGFR2 genetic alterations were detected by reverse transcription-PCR and direct sequence. An association of FGFR2 expression with clinicopathological features was investigated in cHCC-CCAs. FGFR2 expression was detected in significantly more patients with cHCC-CCA (21.3%) and small duct-type iCCA (25.7%), compared to those with large duct-type iCCA (3.3%) and HCC (0%) (p < 0.05). FGFR2-positive cHCC-CCAs were significantly smaller size (p < 0.05), with more predominant cholangiolocarcinoma component (p < 0.01) and less nestin expression (p < 0.05). Genetic alterations of ARID1A and BAP1 and multiple genes were significantly more frequent in FGFR2-positive cHCC-CCAs (p < 0.05). 5'/3' imbalance in FGFR2 genes indicating exon18-truncated FGFR2 was significantly more frequently detected in FGFR2-positive cHCC-CCAs and small duct iCCAs, compared to FGFR2-negative ones (p < 0.05). FGFR2::BICC fusion was detected in a case of cHCC-CCAs. FGFR2 genetic alterations may be prevalent in cHCC-CCAs as well as small duct-type iCCAs, which suggest cHCC-CCAs may also be a possible therapeutic target of FGFR2 inhibitors., (© 2024. The Author(s).)

Recent advances in the treatment of gastric cancer (GC) with chemotherapy, immunotherapy, anti-angiogenic therapy and targeted therapies have yielded some improvement in survival outcomes; however, metastatic GC remains a lethal malignancy and amongst the leading causes of cancer-related mortality worldwide. Importantly, the ongoing molecular characterisation of GCs continues to uncover potentially actionable molecular targets. Among these, aberrant FGFR2-driven signalling, predominantly arising from FGFR2 amplification, occurs in approximately 3-11% of GCs. However, whilst several inhibitors of FGFR have been clinically tested to-date, there are currently no approved FGFR-directed therapies for GC. In this review, we summarise the significance of FGFR2 as an actionable therapeutic target in GC, examine the recent pre-clinical and clinical data supporting the use of small-molecule inhibitors, antibody-based therapies, as well as novel approaches such as proteolysis-targeting chimeras (PROTACs) for targeting FGFR2 in these tumours, and discuss the ongoing challenges and opportunities associated with their clinical development.

Background: Genetic abnormalities in the FGFR signalling occur in 40% of breast cancer (BCa) patients resistant to anti-ER therapy, which emphasizes the potential of FGFR-targeting strategies. Recent findings indicate that not only mutated FGFR is a driver of tumour progression but co-mutational landscapes and other markers should be also investigated. Autophagy has been recognized as one of the major mechanisms underlying the role of tumour microenvironment in promotion of cancer cell survival, and resistance to anti-ER drugs. The selective autophagy receptor p62/SQSTM1 promotes Nrf-2 activation by Keap1/Nrf-2 complex dissociation. Herein, we have analysed whether the negative effect of FGFR2 on BCa cell response to anti-ER treatment involves the autophagy process and/or p62/Keap1/Nrf-2 axis., Methods: The activity of autophagy in ER-positive MCF7 and T47D BCa cell lines was determined by analysis of expression level of autophagy markers (p62 and LC3B) and monitoring of autophagosomes' maturation. Western blot, qPCR and proximity ligation assay were used to determine the Keap1/Nrf-2 interaction and Nrf-2 activation. Analysis of 3D cell growth in Matrigel® was used to assess BCa cell response to applied treatments. In silico gene expression analysis was performed to determine FGFR2/Nrf-2 prognostic value., Results: We have found that FGFR2 signalling induced autophagy in AMPKα/ULK1-dependent manner. FGFR2 activity promoted dissociation of Keap1/Nrf-2 complex and activation of Nrf-2. Both, FGFR2-dependent autophagy and activation of Nrf-2 were found to counteract the effect of anti-ER drugs on BCa cell growth. Moreover, in silico analysis showed that high expression of NFE2L2 (gene encoding Nrf-2) combined with high FGFR2 expression was associated with poor relapse-free survival (RFS) of ER+ BCa patients., Conclusions: This study revealed the unknown role of FGFR2 signalling in activation of autophagy and regulation of the p62/Keap1/Nrf-2 interdependence, which has a negative impact on the response of ER+ BCa cells to anti-ER therapies. The data from in silico analyses suggest that expression of Nrf-2 could act as a marker indicating potential benefits of implementation of anti-FGFR therapy in patients with ER+ BCa, in particular, when used in combination with anti-ER drugs., (© 2024. The Author(s).)

Objective: We present perinatal imaging findings of a fetus with Pfeiffer syndrome and a heterozygous c.1019A>G, p.Tyr340Cys (Y340C) mutation in FGFR2 presenting a cloverleaf skull, craniosynostosis and short limbs on prenatal ultrasound mimicking thanatophoric dysplasia type II (TD2)., Case Report: A 37-year-old, gravida 2, para 1, woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XY. However, craniofacial anomaly was found on prenatal ultrasound at 21 weeks of gestation, which showed a cloverleaf skull with severe craniosynostosis and relatively short straight long bones. Fetal magnetic resonance imaging (MRI) analysis at 22 weeks of gestation showed a cloverleaf skull, proptosis and relatively shallowing of the sylvian fissures. Prenatal ultrasound at 24 weeks of gestation showed a fetus with a cloverleaf skull with a biparietal diameter (BPD) of 6.16 cm (equivalent to 24 weeks), an abdominal circumference (AC) of 18.89 cm (equivalent to 24 weeks) and a femur length (FL) of 3.65 cm (equivalent to 21 weeks). A tentative diagnosis of TD2 was made. The pregnancy was subsequently terminated, and a 928-g malformed fetus was delivered with severe craniosynostosis, proptosis, midface retrusion, a cloverleaf skull, broad thumbs and broad big toes. The broad thumbs were medially deviated. Whole body X-ray showed a cloverleaf skull and straight long bones. However, molecular analysis of FGFR3 on the fetus revealed no mutation in the target regions. Subsequent whole exome sequencing (WES) on the DNA extracted from umbilical cord revealed a heterozygous c.1019A>G, p.Tyr340Cys (Y340C) mutation in the FGFR2 gene., Conclusion: Fetuses with a Y340C mutation in FGFR2 may present a cloverleaf skull on prenatal ultrasound, and WES is useful for a rapid differential diagnosis of Pfeiffer syndrome from TD2 under such a circumstance., (Copyright © 2024. Published by Elsevier B.V.)

Background: Klippel-Feil syndrome (KFS) is a rare congenital disorder characterized by the fusion of two or more cervical vertebrae during early prenatal development. This fusion results from a failure of segmentation during the first trimester. Although six genes have previously been associated with KFS, they account for only a small proportion of cases. Among the distinct subtypes of KFS, "sandwich fusion" involving concurrent fusion of C0-1 and C2-3 vertebrae is particularly noteworthy due to its heightened risk for atlantoaxial dislocation. In this study, we aimed to investigate novel candidate mutations in patients with "sandwich fusion.", Methods: We collected and analyzed clinical data from 21 patients diagnosed with "sandwich fusion." Whole-exome sequencing (WES) was performed, followed by rigorous bioinformatics analyses. Our focus was on the six known KFS-related genes (GDF3, GDF6, MEOX1, PAX1, RIPPLY2, and MYO18). Suspicious mutations were subsequently validated through in vitro experiments., Results: Our investigation revealed two novel exonic mutations in the FGFR2 gene, which had not previously been associated with KFS. Notably, the c.1750A > G variant in Exon 13 of FGFR2 was situated within the tyrosine kinase domain of the protein, in close proximity to several established post-translational modification sites. In vitro experiments demonstrated that this certain mutation significantly impacted the function of FGFR2. Furthermore, we identified four heterozygous candidate variants in two genes (PAX1 and MYO18B) in two patients, with three of these variants predicted to have potential clinical significance directly linked to KFS., Conclusions: This study encompassed the largest cohort of patients with the unique "sandwich fusion" subtype of KFS and employed WES to explore candidate mutations associated with this condition. Our findings unveiled novel variants in PAX1, MYO18B, and FGFR2 as potential risk mutations specific to this subtype of KFS., (© 2024. The Author(s).)

Objective: Fibroblast growth factor receptor-2 (FGFR2) and miR-889-3p expression in oral squamous cell carcinoma (OSCC) tumours were compared to normal controls. We then examined the relationship between miR-889-3p, FGFR2 expression and patient clinicopathological features., Materials and Methods: The interaction of FGFR2 and miR-889-3p was investigated using bioinformatics. Then, OSCC tumour biopsies and normal gingiva were collected and processed for expression analysis of FGFR2-specific mRNA and miR-889-3p using real-time PCR. Immunohistochemistry evaluated the expression of the FGFR2 protein., Results: The protein and mRNA expression levels of FGFR2 were significantly greater in tumours when contrasted with controls. Expression of miR-889-3p was significantly lower in OSCC compared to normal tissues. The FGFR2 and miR-889-3p expressions were inversely related (-0.86 and -0.73, respectively) in both cases and controls. Changes in miR-889-3p and FGFR2 expression in tumour tissues were associated with lymph node metastasis (LNM), with ~0.57 and ~3.0 folds of change in positive-LNM patients, respectively., Conclusion: Decreased expression of miR-889-3p in OSCC tumours suggests that miR-889-3p functions as a tumour suppressor gene. Overexpression of FGFR2 further proves the role of miR-889-3p in the regulation of the FGFR2 pathway. This was further confirmed by showing differences in miR-889-3p expression in positive and negative LNM cases., (© 2024 Wiley Periodicals LLC.)

Background: Ovarian cancer (OC) is distinguished by its aggressive nature and the limited efficacy of current treatment strategies. Recent studies have emphasized the significant role of cancer-associated fibroblasts (CAFs) in OC development and progression., Methods: Employing sophisticated machine learning techniques on bulk transcriptomic datasets, we identified fibroblast growth factor 7 (FGF7), derived from CAFs, as a potential oncogenic factor. We investigated the relationship between FGF7 expression and various clinical parameters. A series of in vitro experiments were undertaken to evaluate the effect of CAFs-derived FGF7 on OC cell activities, such as proliferation, migration, and invasion. Single-cell transcriptomic analysis was also conducted to elucidate the interaction between FGF7 and its receptor. Detailed mechanistic investigations sought to clarify the pathways through which FGF7 fosters OC progression., Results: Our findings indicate that higher FGF7 levels correlate with advanced tumor stages, increased vascular invasion, and poorer prognosis. CAFs-derived FGF7 significantly enhanced OC cell proliferation, migration, and invasion. Single-cell analysis and in vitro studies revealed that CAFs-derived FGF7 inhibits the ubiquitination and degradation of hypoxia-inducible factor 1 alpha (HIF-1α) via FGFR2 interaction. Activation of the FGF7/HIF-1α pathway resulted in the upregulation of mesenchymal markers and downregulation of epithelial markers. Importantly, in vivo treatment with neutralizing antibodies targeting CAFs-derived FGF7 substantially reduced tumor growth., Conclusion: Neutralizing FGF7 in the medium or inhibiting HIF-1α signaling reversed the effects of FGF7-mediated EMT, emphasizing the dependence of FGF7-mediated EMT on HIF-1α activation. These findings suggest that targeting the FGF7/HIF-1α/EMT axis may offer new therapeutic opportunities to intervene in OC progression., (© 2024. The Author(s).)

Comprehensive genome profiling (CGP) is expected to widen the scope of cancer drug options by identifying the genes involved in carcinogenesis. However, a few patients can access recommended treatments following CGP. Herein, we report a case in which pemigatinib, a selective fibroblast growth factor receptor (FGFR) inhibitor, was used as last-line therapy to treat a patient with advanced gastric cancer exhibiting FGFR2 genomic alterations, as determined by CGP testing. The patient (male, 52 years old) was diagnosed with advanced gastric cancer (cStage IV, cT4aN3M1 [LYM], por, HER2 0, microsatellite stable) and received docetaxel + cisplatin + S-1 (7 cycles), irinotecan + ramucirumab (11 cycles), and nivolumab (3 cycles), but experienced progressive disease (PD). Subsequently, FoundationOne Liquid CDx testing was conducted, revealing FGFR2 rearrangement and amplification; however, no clinical trials on genotype-matched therapies for FGFR2 alterations were available. After three cycles of TAS-102, the patient experienced PD and provided consent for the off-label use of pemigatinib. The Cancer Genomics Medical Committee of our hospital approved the self-funded treatment. The patient had markedly decreased CEA and CA19-9 levels after treatment initiation, but experienced PD after five courses. Over the treatment course, grade 1 hyperphosphatemia and onychomadesis were observed. To the best of our knowledge, this is the first reported case of pemigatinib therapy employed in a patient with advanced gastric cancer exhibiting FGFR2 gene alterations. This case could serve as a notable example of tumor-agnostic therapy to broaden treatment options for gastric cancer patients with rare genetic alterations., Competing Interests: Conflict of interestThe authors declare no competing financial interests., (© The Author(s) under exclusive licence to The Japan Society of Clinical Oncology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Aims: Oncogenic FGFR1/2/3 rearrangements are found in various cancers. Reported cases in head and neck (HN) are mainly squamous cell carcinomas (SCCs) with FGFR3::TACC3 fusions, a subset of which also harbour high-risk human papillomavirus (HPV). However, the knowledge of the clinicopathological spectrum of FGFR-rearranged head and neck carcinomas (FHNC) is limited., Methods and Results: A retrospective MSK-fusion clinical sequencing cohort 2016-23 was searched to identify malignant tumours in the HN region harbouring FGFR1/2/3 fusion. FHNC were characterised by histological examination, immunohistochemistry and molecular analysis. Electronic medical records were reviewed. Three FHNC were identified. Two cases (cases 1 and 2) involved sinonasal tract and were high-grade carcinomas with squamous, basaloid, glandular and/or ductal-myoepithelial features. Case 1 arose in a 79-year-old man and harboured FGFR2::KIF1A fusion. Case 2 arose in a 58-year-old man, appeared as HPV-related multiphenotypic sinonasal carcinoma (HMSC), and was positive for FGFR2::TACC2 fusion and concurrent high-risk HPV, non-type 16/18. Case 3 was FGFR3::TACC3 fusion-positive keratinising SCCs arising in the parotid of a 60-year-old man. All three cases presented at stage T4. Clinical follow-up was available in two cases; case 1 remained disease-free for 41 months post-treatment and case 3 died of disease 2 months after the diagnosis., Conclusions: FHNC include a morphological spectrum of carcinomas with squamous features and may occur in different HN locations, such as parotid gland and the sinonasal tract. Sinonasal cases can harbour FGFR2 rearrangement with or without associated high-risk HPV. Timely recognition of FHNC could help select patients potentially amenable to targeted therapy with FGFR inhibitors. Further studies are needed (1) to determine if FGFR2 rearranged/HPV-positive sinonasal carcinomas are biologically distinct from HMSC, and (2) to elucidate the biological and clinical significance of FGFR2 rearrangement in the context of high-risk HPV., (© 2023 John Wiley & Sons Ltd.)

Craniosynostosis is a common yet complex birth defect, characterized by premature fusion of the cranial sutures that can be syndromic or nonsyndromic. With over 180 syndromic associations, reaching genetic diagnoses and understanding variations in underlying cellular mechanisms remains a challenge. Variants of FGFR2 are highly associated with craniosynostosis and warrant further investigation. Using the missense mutation FGFR2 W290R , an effective mouse model of Crouzon syndrome, craniofacial features were analyzed using geometric morphometrics across developmental time (E10.5-adulthood, n = 665 total). Given the interrelationship between the cranial vault and basicranium in craniosynostosis patients, the basicranium and synchondroses were analyzed in perinates. Embryonic time points showed minimal significant shape differences. However, hetero- and homozygous mutant perinates and adults showed significant differences in shape and size of the cranial vault, face, and basicranium, which were associated with cranial doming and shortening of the basicranium and skull. Although there were also significant shape and size differences associated with the basicranial bones and clear reductions in basicranial ossification in cleared whole-mount samples, there were no significant alterations in chondrocyte cell shape, size, or orientation along the spheno-occipital synchondrosis. Finally, shape differences in the cranial vault and basicranium were interrelated at perinatal stages. These results point toward the possibility that facial shape phenotypes in craniosynostosis may result in part from pleiotropic effects of the causative mutations rather than only from the secondary consequences of the sutural defects, indicating a novel direction of research that may shed light on the etiology of the broad changes in craniofacial morphology observed in craniosynostosis syndromes., (© 2024 The Authors. The Anatomical Record published by Wiley Periodicals LLC on behalf of American Association for Anatomy.)

To develop radiolabeled FGFR2-targeting probes for visualizing fibroblast growth factor receptor (FGFR) expression levels in the tumor microenvironment, four novel 99m Tc-labeled FGFR2-targeting peptides ([ 99m Tc]Tc-FGFR2-1, [ 99m Tc]Tc-FGFR2-2, [ 99m Tc]Tc-FGFR2-3, and [ 99m Tc]Tc-FGFR2-4) with different amino acid linkers between the targeted peptide moiety and the 99m Tc chelating group were designed and synthesized. The in vitro cellular inhibition, internalization, and efflux results demonstrated that the four 99m Tc complexes exhibited FGFR2-specific binding and prolonged cellular retention in DU145 human prostate cancer cells, which indicated that modification from the glycine side (N-terminal) of CH02 was feasible. Among them, [ 99m Tc]Tc-FGFR2-1 exhibited the highest in vitro cellular uptake and in vivo tumor uptake at 30 min postinjection, and tumor uptake could be significantly inhibited by the competitor CH02 (53% inhibited, p < 0.05), suggesting the tumor-specific targeting ability of [ 99m Tc]Tc-FGFR2-1. The DU145-xenografted tumor lesions were clearly visualized by single photon emission computed tomography (SPECT)/CT at 30 min postinjection of [ 99m Tc]Tc-FGFR2-1, highlighting its potential as a SPECT imaging probe for tumor FGFR2 detection.

Nickel, a common environmental hazard, is a risk factor for craniosynostosis. However, the underlying biological mechanism remains unclear. Here, we found that early-life nickel exposure induced craniosynostosis in mice. In vitro, nickel promoted the osteogenic differentiation of human mesenchymal stem cells (hMSCs), and its osteogenic ability in vivo was confirmed by an ectopic osteogenesis model. Further mRNA sequencing showed that ERK1/2 signaling and FGFR2 were aberrantly activated. FGFR2 was identified as a key regulator of ERK1/2 signaling. By promoter methylation prediction and methylation-specific PCR (MSP) assays, we found that nickel induced hypomethylation in the promoter of FGFR2, which increased its binding affinity to the transcription factor Sp1. During pregnancy and postnatal stages, AZD4547 rescued nickel-induced craniosynostosis by inhibiting FGFR2 and ERK1/2. Compared with normal individuals, nickel levels were increased in the serum of individuals with craniosynostosis. Further logistic and RCS analyses showed that nickel was an independent risk factor for craniosynostosis with a nonlinear correlation. Mediated analysis showed that FGFR2 mediated 30.13% of the association between nickel and craniosynostosis risk. Collectively, we demonstrate that early-life nickel exposure triggers the hypomethylation of FGFR2 and its binding to Sp1, thereby promoting the osteogenic differentiation of hMSCs by ERK1/2 signaling, leading to craniosynostosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Gastric adenocarcinoma is a prevalent form of cancer that often remains undetected in its early stages due to the lack of specific symptoms. This delayed diagnosis leads to poor clinical outcomes, underscoring the need for an effective and non-invasive method for early detection. Recent advances in cancer epigenetics have led to the identification of biomarkers that have the potential to revolutionize the early detection and monitoring of this disease. One such promising biomarker is the methylation of the FGFR2 promoter. This study aims to measure the methylation levels of a specific CpG site in the FGFR2 promoter gene in DNA extracted from blood leukocytes from patients with intestinal metaplasia, gastric cancer, and healthy control., Material and Methods: The CpG site of the FGFR2 gene promoter was identified in its control region. Methylation alteration of the selected FGFR2 CpG site was determined through the (methylation-sensitive restriction enzyme) MSRE-qPCR. Genomic DNA was extracted from one hundred twenty-five participants., Results: The normal group had mean methylation levels of 93.23 ± 4.929%, while the IM group had a level of 69.85 ± 27.15%. In GC patients, the levels varied, with 25.96 ± 18.98% in the intestinal type and 28.30 ± 16.07% in the diffuse type. The methylation levels in the IM and GC patients were significantly lower than those in the normal control group. However, no significant difference was observed between the methylation status of the intestinal type of GC and the diffuse type. The Receiver operating characteristic (ROC) curve analysis showed that FGFR2 CpG methylation levels in GC patients compared to normal controls had a high sensitivity of 100% and specificity of 100%, with a cut-off of < 74.25%; when GC patients were compared to IM patients, the sensitivity was 85%, and the specificity was 80%, with a cut-off < 44.45%., Conclusions: The potential of the FGFR2 methylation status as a non-invasive biomarker lies in its ability to be detected in blood leukocytes, which makes it a promising tool for the early detection of intestinal metaplasia and gastric cancer. This could significantly improve the detection and management of these gastric conditions., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Fibroblast growth factor receptor (FGFR) signaling is a key modulator of cellular processes dysregulated in cancer. We recently found that the high expression of the mesenchymal FGFR2c variant in human pancreatic ductal adenocarcinoma (PDAC)-derived cells triggers the PKCε-mediated improvement of EMT and of MCL-1/SRC-dependent cell invasion. Since other membrane proteins can affect the receptor tyrosine kinase signaling, including transient receptor potential channels (TRPs), in this work, we investigated the role of TRPs in the FGFR2c/PKCε oncogenic axis. Our results highlighted that either the FGFR2c/PKCε axis shut-off obtained by shRNA or its sustained activation via ligand stimulation induces TRPA1 downregulation, suggesting a channel/receptor dependence. Indeed, biochemical molecular and immunofluorescence approaches demonstrated that the transient depletion of TRPA1 by siRNA was sufficient to attenuate FGFR2c downstream signaling pathways, as well as the consequent enhancement of EMT. Moreover, the biochemical check of MCL1/SRC signaling and the in vitro assay of cellular motility suggested that TRPA1 also contributes to the FGFR2c-induced enhancement of PDAC cell invasiveness. Finally, the use of a selective channel antagonist indicated that the contribution of TRPA1 to the FGFR2c oncogenic potential is independent of its pore function. Thus, TRPA1 could represent a putative candidate for future target therapies in PDAC.

Intrahepatic cholangiocarcinoma (ICCA) is a rare and aggressive malignant tumor that arises from the biliary tracts in the liver. Upfront surgery with adjuvant capecitabine in patients with resectable disease is often the standard treatment. Unfortunately, only 20% of patients present with resectable disease and many individuals will develop recurrence or metastatic disease after curative-intent resection. Patients with advanced or metastatic ICCA often require multidisciplinary care with a combination of cytotoxic chemotherapy, targeted therapy, and/or locoregional therapies. Gemcitabine plus cisplatin is currently first line therapy for advanced or metastatic ICCA. In recent years, efforts have been focused to develop more effective targeted therapy, most commonly with FGFR and IDH inhibitors for ICCA. Despite these efforts, ICCA still carries a poor prognosis. We herein review the current clinical management of ICCA focusing on surgical technique and systemic therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ruff and Pawlik.)

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer accounting for 90% of cases. It is a highly invasive and deadly cancer with a gradual onset. Polypyrimidine tract-binding protein 1 (PTBP1) is an important RNA-binding protein involved in RNA metabolism and has been linked to oncogenic splicing events. While the oncogenic role of PTBP1 in HCC cells has been established, the exact mechanism of action remains unclear. This study aimed to investigate the functional connection between PTBP1 and dysregulated splicing events in HCC. Through immunoprecipitation-mass spectrometry analyses, we discovered that the proteins bound to PTBP1 were significantly enriched in the complex responsible for the alternative splicing of FGFR2 (fibroblast growth factor receptor 2). Further RNA immunoprecipitation and quantitative PCR assays confirmed that PTBP1 down-regulated the FGFR2-IIIb isoform levels and up-regulated the FGFR2-IIIc isoform levels in HCC cells, leading to a switch from FGFR2-IIIb to FGFR2-IIIc isoforms. Subsequent functional evaluations using CCK-8, transwell, and plate clone formation assays in HCC cell lines HepG2 and Huh7 demonstrated that FGFR2-IIIb exhibited tumor-suppressive effects, while FGFR2-IIIc displayed tumor-promoting effects. In conclusion, this study provides insights into the PTBP1-mediated alternative splicing mechanism in HCC progression, offering a new theoretical basis for the prevention and treatment of this malignancy. Mechanistically, the isoform switch from FGFR2-IIIb to FGFR2-IIIc promoted epithelial-mesenchymal transformation (EMT) of HCC cells and activated the FGFR cascades ERK and AKT pathways.

Breast cancer mortality results from incurable recurrences thought to be seeded by dormant, therapy-refractory residual tumor cells (RTCs). Understanding the mechanisms enabling RTC survival is therefore essential for improving patient outcomes. Here, we derive a dormancy-associated RTC signature that mirrors the transcriptional response to neoadjuvant therapy in patients and is enriched for extracellular matrix-related pathways. In vivo CRISPR-Cas9 screening of dormancy-associated candidate genes identifies the galactosyltransferase B3GALT6 as a functional regulator of RTC fitness. B3GALT6 is required for glycosaminoglycan (GAG) linkage to proteins to generate proteoglycans, and its germline loss of function in patients causes skeletal dysplasias. We find that B3GALT6-mediated biosynthesis of heparan sulfate GAGs predicts poor patient outcomes and promotes tumor recurrence by enhancing dormant RTC survival in multiple contexts, and does so via a B3GALT6-heparan sulfate/HS6ST1-heparan 6-O-sulfation/FGF1-FGFR2 signaling axis. These findings implicate B3GALT6 in cancer and nominate FGFR2 inhibition as a promising approach to eradicate dormant RTCs and prevent recurrence., Competing Interests: Declaration of interests L.A.C. has served as an expert consultant to Teva Pharmaceuticals, Eisai, Sanofi, Eli Lilly, Whittaker, Clark and Daniels, Wyeth, Imerys, Colgate, Becton Dickinson, Sterigenics, and the U.S. Department of Justice in litigation., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In general, endometrioid-defining features such as squamoid morular metaplasia are not thought to be associated with mesonephric adenocarcinoma (MA) and mesonephric-like adenocarcinoma (MLA). Here, we report a case of FGFR2-mutated ovarian MLA with squamoid morular metaplasia accompanied by aberrant nuclear and cytoplasmic β-catenin expression and CTNNB1 mutation. Histologically, the tumor showed classical MLA histology, including well-formed glands with intraluminal eosinophilic secretions and cells with papillary thyroid carcinoma-like nuclei. Squamoid morular metaplasia was intimately associated with the tumor. Glandular epithelial elements, including those immediately associated with the squamoid morules, were negative for ER, but positive for both GATA3 and PAX8; aberrant β-catenin expression was limited to the squamoid morules. This case illustrates the ability of mesonephric neoplasia to exhibit histological features previously thought to be restricted to an endometrioid phenotype., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Fibroblast growth factor receptor (FGFR)2 expression was decreased in hypertension patients while its role in hypertension was not explored. This experiment aimed to investigate the expression ofFGFR2 in angiotensin II (Ang II)-induced human umbilical vein endothelial cells (HUVECs) and the role of FGFR2 in improving AngII-induced hypertension-related endothelial dysfunction., Methods: AngII-induced HUVECs simulated the hypertension model in vitro. The expression of FGFR2 in Ang II-induced HUVECs and transfected HUVECswas detected by RT-qPCR and western blot. The viability, apoptosis, migration and tube formation ability of Ang II-induced HUVECs were analyzed by Methyl Thiazolyl Tetrazolium (MTT) assay, flow cytometry analysis, wound healing assay and tube formation assay.Detectionof lactate dehydrogenase (LDH), caspase 3, Nitric Oxide (NO) and oxidative stress levels was conducted by assay kits and reactive oxygen species (ROS) level was detected by DCFH-DA assay. The expression of apoptosis-related proteins, protein kinase B(Akt)/nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway-related proteins, phospho(p)-endothelial nitric oxide synthase (eNOS) and eNOS was determined by western blot., Results: The expression of FGFR2 was decreased in Ang II-induced HUVECs. FGFR2overexpression increased viability, suppressed apoptosis and oxidative stress, and improve endothelial dysfunction of AngII-induced HUVECs through activating the Akt/Nrf2/ARE signaling pathway. MK-2206 (Akt inhibitor) could weaken the effect of FGFR2overexpression to reduce viability, promote apoptosis and oxidative stress, and aggravate endothelial dysfunction of Ang II-inducedHUVECs., Conclusion: Inconclusion, FGFR2activated the Akt/Nrf2/ARE signaling pathway to improve AngII-induced hypertension-related endothelial dysfunction.

Osteoporosis is a systemic, multifactorial disorder of bone mineralization. Many factors contributing to the development of osteoporosis have been identified so far, including gender, age, nutrition, lifestyle, exercise, drug use, as well as a range of comorbidities. In addition to environmental and lifestyle factors, molecular genetic factors account for 50-85% of osteoporosis cases. For example, the vitamin D receptor (VDR), collagen type I (COL1), estrogen receptor (ER), apolypoprotein Е (ApoE), bone morphogenetic protein (BMP), and Low-density lipoprotein receptor-related protein 5 (LRP5) are all involved in the pathogenesis of osteoporosis. Among the candidate genes, the pathogenic variants in which are involved in the pathogenesis of osteoporosis is FGFR2. Additionally, FGFs/FGFRs-dependent signaling has been shown to regulate skeletal development and has been linked to a plethora of heritable disorders of the musculoskeletal system. In this study we present the clinical, biochemical and radiological findings, as well as results of molecular genetic testing of a 13-year-old male proband with heritable osteoporosis, arthralgia and multiple fractures and a family history of abnormal bone mineralization and fractures. Whole exome sequencing found a heterozygous previously undescribed variant in the FGFR2 gene (NM&#95;000141.5) (GRCh37.p13 ENSG00000066468.16: g.123298133dup; ENST00000358487.5:c.722dup; ENSP00000351276.5:p.Asn241LysfsTer43). The same variant was found in two affected relatives. These data lead us to believe that the variant in FGFR2 found in our proband and his relatives could be related to their phenotype. Therefore, modern methods of molecular genetic testing can allow us to differentiate between osteogenesis imperfecta and other bone mineralization disorders., (© 2023. The Author(s).)