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The FGFR1 V561M mutation significantly reduces the efficacy of current FGFR1 inhibitors, creating an urgent need for targeted second-generation therapies. In this study, we developed a comprehensive virtual screening protocol that combines energy-based screening and machine learning techniques, leading to the identification of a novel compound, Show less

This study aims to develop a receptor-dependent 4D-QSAR model to overcome key limitations of traditional QSAR, including its dependency on molecular alignment and poor performance with small datasets, by integrating ligand - target interaction information. Angiogenesis-related receptors, including VEGFR2, FGFR1-4, EGFR, PDGFR, RET, and HGFR (MET) were chosen based on the biological relevance in cancer. Ligand datasets with known IC₅₀ values were extracted from PubChem. One hundred docked conformers per ligand were generated using AutoDock. Protein - ligand interaction fingerprints were computed and encoded as 4D-descriptors. After evaluation via multiple classification algorithms, Random Forest was selected for model construction. The results shown that the proposed model outperformed traditional 2D-QSAR approaches across all targets. Accuracy exceeded 70% in most datasets, including those with fewer than 30 compounds. Besides, the model performance was significantly improved via using all conformers versus using a single best pose. The model demonstrated robust predictive power across varying receptor classes under consistent assay conditions. The proposed receptor-dependent 4D-QSAR model provides enhanced accuracy and generalizability for small, diverse datasets. Its integration of LTI-derived descriptors makes it a valuable tool for early-stage lead optimization and supports rational multi-target drug design in oncology. Show less

To identify gene alterations in circulating tumor DNA (ctDNA) from palbociclib-treated patients with advanced or metastatic breast cancer (ABC) in POLARIS to identify potential mutagenic drivers of resistance. POLARIS was a prospective, real-world study of palbociclib in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) ABC in the United States and Canada. Patients who received ≥1 palbociclib dose and had ≥1 ctDNA measurement were included in the biomarker analysis. ctDNA samples were analyzed using the Guardant360 platform (73 genes) at baseline, cycle 2 day 1 (C2D1), and end of treatment (EOT). Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs. A total of 344 patients were included in the biomarker analysis. Gene alterations were detected in 85% (286 of 336) of baseline samples, 72% (201 of 278) of C2D1 samples, and 85% (88 of 104) of EOT samples. The most frequently mutated genes were Patients without altered Show less

Idiopathic hypereosinophilic syndrome (iHES) is a rare hematologic condition characterized by persistent, unexplained eosinophilia and organ involvement. Its diagnosis is challenging due to overlapping features with other eosinophilic and inflammatory gastrointestinal disorders. We report a case of a 44-year-old male with a history of asthma who presented with chronic epigastric pain, rectal bleeding, and significant weight loss. Initial investigations, including elevated CRP and fecal calprotectin, suggested inflammatory bowel disease, and treatment was initiated accordingly. However, symptoms persisted, and further evaluations revealed marked eosinophilic infiltration in gastric and colonic biopsies, raising suspicion for eosinophilic gastroenteritis. Repeat endoscopy showed giant gastric folds with significant eosinophilic infiltration (>120 eosinophils/HPF). Imaging demonstrated gastrointestinal wall thickening, biliary involvement, and incidental pulmonary nodules. Bone marrow biopsy revealed preserved trilineage hematopoiesis with prominent eosinophilia. Infectious, autoimmune, allergic, and neoplastic causes were systematically excluded. Cytogenetic testing was negative for PDGFRA, PDGFRB, and FGFR1 mutations, ruling out clonal eosinophilic disorders. Based on persistent peripheral eosinophilia, histologic evidence of tissue infiltration, and exclusion of secondary or clonal causes, a diagnosis of iHES was established in accordance with WHO 2024 criteria. The patient started on systemic corticosteroids, achieving partial symptom relief. Due to relapse during steroid tapering, azathioprine was added as a steroid-sparing agent. Ongoing monitoring was planned with consideration of biologic therapy for future relapses. This case illustrates the diagnostic complexity of iHES presenting with gastrointestinal involvement mimicking inflammatory bowel disease. It highlights the importance of a structured diagnostic approach, including repeated tissue evaluation and hematologic assessment, in differentiating iHES from other eosinophilic and inflammatory disorders. Show less

The high mortality rate of severe heat stroke is mainly related to multiple organ dysfunction syndrome (MODS), and respiratory failure caused by acute lung injury (ALI) is a significant factor in the development of MODS during the course of severe heat stroke. Previous research has demonstrated that severe heat stroke-induced acute lung injury (sHS-ALI) is associated with an increase in reactive oxygen species (ROS) in vascular endothelial cells (VECs), but the specific initiating factors and intermediate mechanisms involved are unclear. In this study, the mRNA profiles of mouse lung tissues were analysed using high-throughput sequencing. Genome-wide knockout was performed using CRISPR-Cas9 technology to identify a cohort of differentially expressed genes that promote human umbilical vein endothelial cells survival after heat stress. The expression of key proteins [fibroblast growth factor 23 (FGF23), phosphorylated fibroblast growth factor receptor-1 (p-FGFR-1), FGFR-1, phosphorylated phospholipase C-γ2 (p-PLC-γ2), PLC-γ2, p-p47 In this study, we first screened sHS-ALI target genes by cross-comparison This study confirmed that FGF23/FGFR1 signalling, as an upstream priming factor, mediated NOX2-ROS activation in VECs after heat stress, thus participating in the sHS-ALI process. FGFR-1 Y766 phosphorylation is essential for FGF23/FGFR-1 signalling activation in VECs, which is involved in sHS-ALI. These findings further clarify the mechanism underlying sHS-ALI and contribute to reducing the mortality and morbidity of severe heat stroke. Show less

The study evaluated the association of Case-control study. Brazilian Oral Cleft Group. The study included 881 healthy controls and 800 patients with different types of NSOC: 232 with cleft lip only (NSCLO), 568 with cleft lip and palate (NSCLP), and 274 with cleft palate only (NSCPO). The genomic DNA was genotyped with allelic discrimination assays for five Although only nominal Our results demonstrate an increased risk of NSCL  ±  P in Brazilian individuals with enrichment of African ancestry in the presence of the Show less

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer related deaths globally. Despite advancements in treatment, drug resistance and adverse side effects have spurred the search for novel therapeutic strategies. This study aimed to investigate how the Show less

Lung squamous cell carcinoma (LUSC), a subset of non-small cell lung cancer (NSCLC), accounts for about 30% of all lung cancers (LC) and exhibits a dismal response to current therapeutic protocols. Existed studies have indicated that aberrations in fibroblast growth factor receptors (FGFRs) play a pivotal role in the progression of LUSC, rendering them as attractive targets for therapeutic intervention in this cancer type. This study found that Erdafitinib (Erda), a novel pan-FGF receptor tyrosine kinase inhibitor (TKI), exerted a cytotoxic effect on LUSC cells. However, STAT3, the downstream target of FGFRs, remained still activated despite Erdafitinib treatment. Then, a STAT3 inhibitor, Stattic (Sta), was concurrently used with Erdafitinib, and the combined treatment demonstrated a synergistic efficacy in both Show less

The acquisition of ectopic fibroblast growth factor receptor 1 (FGFR1) expression is well documented in prostate cancer (PCa) progression, notably in conferring tumor growth advantage and facilitating metastasis. However, how FGFR1 contributes to PCa progression is not fully revealed. Here we report that ectopic FGFR1 in PCa cells promotes transferrin receptor 1 (TFR1) expression and expands the labile iron pool (LIP), and vice versa. We further demonstrate that FGFR1 stabilizes iron regulatory proteins 2 (IRP2) and therefore, upregulates TFR1 via promoting IRP2 binding to the IRE of TFR1. Deletion of FGFR1 in DU145 cells decreases the LIP, which potentiates the anticancer efficacy of iron chelator. Intriguingly, forced expression of IRP2 in FGFR1 depleted cells reinstates TFR1 expression and LIP, subsequently restoring the tumorigenicity of the cells. Together, our results here unravel a new mechanism by which FGFR1 drives PCa progression and suggest a potential novel target for PCa therapy. Show less

Receptor-binding peptides are promising candidates for tumor target therapy. However, the inability to occupy "hot spots" on the PPI interface and rapid metabolic instability are significant limitations to their clinical application. We investigated a new strategy in which an FGFR1-binding peptide (Pep1) was site-specifically functionalized with the dinitrophenyl (DNP) hapten at the C-terminus. The resulting Pep1-DNP conjugates retained FGFR1 binding affinity and exhibited a similar potency in inhibiting FGF2-dependent cell proliferation, comparable to that of native Pep1 in vitro. In addition, three conjugates could recruit anti-DNP antibodies onto the surface of cancer cells, thereby mediating the CDC efficacy. In vivo pharmacokinetic studies and antitumor studies demonstrated that optimal conjugate Show less

to evaluate the expression of profibrotic markers TGF-1, MMP-9 and FGFR in the epithelium of proximal renal tubules in patients with urolithiasis depending on the composition of the nodule, as well as on the degree of decrease in the glomerular filtration rate (GFR). complex examination of 17 patients with urolithiasis was carried out. Cockcroft-Gault formula for determining the glomerular filtration rate was used to estimate renal function, according to the results of which all patients were divided into 3 groups depending on the stage of GFR. Percutaneous nephrolithotripsy (PNLT) was performed according to the standard technique using laser treatment. The physical and chemical composition of the nodule was determined by polarization microscopy. All patients underwent morphological and morphometric study of nephrobiopsy specimens obtained at creation of puncture passage during PNLT in patients with nephrolithiasis. Immunohistochemical study was performed using profibrotic marker Anti-TGF beta 1 antibody (1:500, Abcam, UK), Anti-MMP-9 antibody (1:500, Abcam, UK), Anti-FGFR-1 1:50, Abcam, UK). Analysis of the results of morphological study revealed a correlation only between morphological manifestations of CPN progression and expression of profibrotic marker TGF-. The increase in TGF- expression is accompanied by more pronounced atrophic changes in the epithelium of proximal renal tubules, which indicates the triggering of tubulointerstitial fibrosis mechanisms and the role of this marker in the progression of chronic kidney disease in patients with urolithiasis. Show less

In this study, the pathogenic genes of depression were calculated and analyzed by bioinformatics method, and then the key genes of Shaoyao Gancao Decoction in the treatment of depression were deduced and predicted through the correlation study with the target of Shaoyao Gancao Decoction. Through the production of LPS depression model mice, drug treatment, behavioral test and hippocampal tissue sample detection, it was found that Shaoyao Gancao Decoction can regulate the levels of IL-10, TNF- α, BDNF, SMAD3, FGFR1 and FGFR2 to improve depression, which can provide a theoretical basis for exploring the efficacy of Shaoyao Gancao Decoction in the treatment of depression. Show less

Diffuse midline gliomas with H3 K27-alteration (DMGH3) are lethal and inoperable brain tumors. Although DMGH3s mainly occur in pediatric patients, they have also occurred in adult patients. This study aimed to analyze the clinicopathological significance of targetable genetic alterations in non-pediatric DMGH3. Next-generation sequencing (NGS) was conducted on 18 non-pediatric DMGH3 patients to analyze additional genetic alterations. The median age at diagnosis was 35 years, and the mean follow-up duration was 762 days. Fourteen cases involved the thalamus-hypothalamus (77.8%). Histologic high-grade features (WHO histologic grade ≥ 3) were observed in 11 (61.1%) patients. H3F3A (H3 K27 M) alterations were identified in all 18 patients using immunohistochemistry and NGS. TP53 mutations were found in 11 patients (61.1%), FGFR1 or PIK3CA in 3 (16.7%), ATRX in 6 (33.3%), NF1 in 4 (22.2%), and KRAS or ATM in 1 (5.6%). TP53 mutations were significantly correlated with high-grade histological features and worse overall survival (OS) (P < 0.05). Despite non-pediatric DMGH3 cases exhibiting superior OS compared to pediatric DMGH3 cases, TP53 mutations were associated with poorer OS outcomes. Notably, FGFR1 and PIK3CA mutations, which have been identified as potential targetable genes, were detected. In conclusion, non-pediatric DMGH3s showed predominant tumor localization within the thalamus and improved prognosis compared to those in pediatric cases, with TP53 alterations correlating with high-grade histology and shorter survival. Genetic profiling, particularly identifying targetable mutations like FGFR1 and PIK3CA, could inform personalized treatment strategies and improve patient outcomes. Show less

Tumor suppressors are well known drivers of cancer invasion and metastasis in metastatic castration sensitive prostate cancer (mCSPC). However, oncogenes are also known to be altered in this state, however the frequency and prognosis of these alterations are unclear. Thus, we aimed to study the spectrum of oncogene mutations in mCSPC and study the significance of these alteration on outcomes. Four hundred and seventy-seven patients with mCSPC were included who underwent next generation sequencing. Oncogene alterations were defined as mutations in A total of 477 patients were included with baseline characteristics with 117 patients (24.5%) harbored a mutation within an oncogene. A total of 172 oncogene mutations were found within the population with the most common being Oncogenes are frequency mutated in mCSPC and associated with aggressive features and inferior outcomes. Future work will need to validate these results to better assess its significance in allowing for personalization of care. Show less

Next-generation sequencing technology has created many new opportunities for clinical diagnostics, but it faces the challenge of functional annotation of identified mutations. Various algorithms have been developed to predict the impact of missense variants that influence oncogenic drivers. However, computational pipelines that handle biological data must integrate multiple software tools, which can add complexity and hinder non-specialist users from accessing the pipeline. Here, we have developed an online user-friendly web server tool PredictONCO that is fully automated and has a low barrier to access. The tool models the structure of the mutant protein in the first step. Next, it calculates the protein stability change, pocket level information, evolutionary conservation, and changes in ionisation of catalytic amino acid residues, and uses them as the features in the machine-learning predictor. The XGBoost-based predictor was validated on an independent subset of held-out data, demonstrating areas under the receiver operating characteristic curve (ROC) of 0.97 and 0.94, and the average precision from the precision-recall curve of 0.99 and 0.94 for structure-based and sequence-based predictions, respectively. Finally, PredictONCO calculates the docking results of small molecules approved by regulatory authorities. We demonstrate the applicability of the tool by presenting its usage for variants in two cancer-associated proteins, cellular tumour antigen p53 and fibroblast growth factor receptor FGFR1. Our free web tool will assist with the interpretation of data from next-generation sequencing and navigate treatment strategies in clinical oncology: https://loschmidt.chemi.muni.cz/predictonco/. Show less

The Sprouty (SPRY) proteins are evolutionary conserved modulators of receptor tyrosine kinase (RTK) signaling. SPRY2 inhibits fibroblast growth factor (FGF) signaling, whereas it enhances epidermal growth factor (EGF) signaling through inhibition of EGF receptor (EGFR) endocytosis, ubiquitination, and degradation. In this study, we analyzed the effects of SPRY2 on endocytosis and degradation of FGF receptor 1 (FGFR1) using two human glioblastoma (GBM) cell lines with different endogenous SPRY2 levels. SPRY2 overexpression (SPRY2-OE) inhibited clathrin- and caveolae-mediated endocytosis of FGFR1, reduced the number of caveolin-1 vesicles and the uptake of transferrin. Furthermore, FGFR1 protein was decreased by SPRY2-OE, whereas EGFR protein was increased. SPRY2-OE enhanced FGFR1 degradation by increased c-casitas b-lineage lymphoma (c-CBL)-mediated ubiquitination, but it diminished binding of phospholipase Cγ1 (PLCγ1) to FGFR1. Consequently, SPRY2-OE inhibited FGF2-induced activation of PLCγ1, whereas it enhanced EGF-induced PLCγ1 activation. Despite the reduction of FGFR1 protein and the inhibition of FGF signaling, SPRY2-OE increased cell viability, and knockdown of SPRY2 enhanced the sensitivity to cisplatin. These results demonstrate that the inhibitory effect of SPRY2-OE on FGF signaling is at least in part due to the reduction in FGFR1 levels and the decreased binding of PLCγ1 to the receptor. Show less

High concentrations of dehydroepiandrosterone sulfate (DHEAS) often precede premature puberty and sometimes polycystic ovary syndrome (PCOS). We hypothesized that the underlying mechanisms might involve DNA methylation. As an indicator of the downstream effects of DHEAS, we looked for associations between prepubertal DHEAS concentration, pubertal progression, and DNA methylation at puberty-related genes in blood cells. Blood methylome and DHEAS concentration at 7.5 and 8.5 years, respectively, were analyzed in 91 boys and 82 girls. Pubertal development data were collected between 8.1 and 17 years (all from UK birth cohort, Avon Longitudinal Study of Parents and Children [ALSPAC]). Correlation between DHEAS and pubertal measurements was assessed by Spearman's correlation. DHEAS association with methylation at individual CpGs or regions was evaluated by linear regression, and nearby genes examined by enrichment analysis and intersection with known puberty-related genes. Boys and girls with higher childhood DHEAS concentrations had more advanced pubic hair growth throughout puberty; girls also had advanced breast development, earlier menarche, and longer menstrual cycles. DHEAS concentration was associated with methylation at individual CpGs near several puberty-related genes. In boys, 14 genes near CpG islands with DHEAS-associated methylation were detected, and in girls, there were 9 which included LHCGR and SRD5A2; FGFR1 and FTO were detected in both sexes. The association between DHEAS and pubertal development, as reported previously, suggests a physiological connection. Our novel findings showing that DHEAS concentration correlates negatively and linearly with DNA methylation levels at regulatory regions of key puberty-related genes, provide a mechanism for such a functional relationship. Show less

Traumatic brain injury (TBI) induces an acute reactive state of microglia, which contribute to secondary injury processes through phagocytic activity and release of cytokines. Several receptor tyrosine kinases (RTK) are activated in microglia upon TBI, and their blockade may reduce the acute inflammation and decrease the secondary loss of neurons; thus, RTKs are potential therapeutic targets. We have previously demonstrated that several members of the Fibroblast Growth Factor Receptor (FGFR) family are transiently phosporylated upon TBI; the availability for drug repurposing of FGFR inhibitors makes worthwhile the elucidation of the role of FGFR in the acute phases of the response to TBI and the effect of FGFR inhibition. A closed, blunt, weight-drop mild TBI protocol was employed. The pan-FGFR inhibitor Rogaratinib was administered to mice 30min after the TBI and daily up to 7 days post injury. Phosphor-RTK Arrays and proteomic antibody arrays were used to determine target engagement and large-scale impact of the FGFR inhibitor. pFGFR1 and pFGFR3 immunostaining were employed for validation. As outcome parameters of the TBI injury immunostainings for NeuN, VGLUT1, VGAT at 7dpi were considered. Inhibition of FGFR during TBI restricted phosphorylation of FGFR1, FGFR3, FGFR4 and ErbB4. Phosphorylation of FGFR1 and FGFR3 during TBI was traced back to Iba1+ microglia. Rogaratinib substantially dowregulated the proteomic signature of the neuroimmunological response to trauma, including the expression of CD40L, CXCR3, CCL4, CCR4, ILR6, MMP3 and OPG. Prolonged Rogaratinib treatment reduced neuronal loss upon TBI and prevented the loss of excitatory (vGLUT+) synapses. The FGFR family is involved in the early induction of reactive microglia in TBI. FGFR inhibition selectively prevented FGFR phosphorylation in the microglia, dampened the overall neuroimmunological response and enhanced the preservation of neuronal and synaptic integrity. Thus, FGFR inhibitors may be relevant targets for drug repurposing aimed at modulating microglial reactivity in TBI. Show less

Encephalocraniocutaneous lipomatosis (ECCL), also known as Haberland syndrome, is a sporadic tumor predisposition neurocutaneous disorder, included in the oculoectodermal syndrome group of mosaic RASopathies. ECCL primarily affects the skin, central nervous system and eyes. Key diagnostic features include nevus psiloliparus, a hallmark subcutaneous lipomatous hamartoma associated with alopecia, along with subcutaneous lipomas, focal skin aplasia, and patchy alopecia. Neurologically, intracranial lipomas, particularly in the cerebellopontine angle, are prevalent, along with cortical dysplasia, ventriculomegaly, and vascular malformations. Ocular findings commonly involve choristomas, lipodermoids, and dermoids, which may impair vision. Diagnosis can be made clinically, but further confirmatory genetic testing can in some cases identify a pathogenic variant in the FGFR1 or KRAS genes. Molecular testing aids diagnosis but is not always conclusive. Management is multidisciplinary with focus on symptomatic management, typically involving dermatological, neurological, and ophthalmologic evaluations with consideration of brain and spine neuroimaging and surgical management of tumors. The prognosis varies, with most individuals leading generally normal lives, though there is a risk of developmental delay, seizures, and low-grade gliomas. The severity of CNS involvement does not consistently correlate with cutaneous or ocular abnormalities. Show less

Lesional focal epilepsy (LFE) is a common and severe seizure disorder caused by epileptogenic lesions, including malformations of cortical development (MCD) and low-grade epilepsy-associated tumors (LEAT). Understanding the genetic etiology of these lesions can inform medical and surgical treatment. We conducted a somatic variant enrichment mega-analysis in brain tissue from 1386 individuals who underwent epilepsy surgery, including 599 previously unpublished individuals with ultra-deep ( > 1600x) targeted panel sequencing. Here we confirm four known associations (BRAF, SLC35A2, MTOR, PTPN11), support eight associations without prior statistical support (FGFR1, PIK3CA, AKT3, NF1, PTEN, RHEB, KRAS, NRAS), and identify novel associations for two genes, DYRK1A and EGFR. Both novel genes show specific histopathological phenotypes, interact with LFE genes and pathways, and may represent promising candidates as biomarkers and potentially druggable targets. Show less

Phospholipase C gamma 2 (PLCγ2) plays important roles in cell signaling downstream of various membrane receptors. PLCγ2 contains a multidomain inhibitory region critical for its regulation, while it has remained unclear how these domains contribute to PLCγ2 activity modulation. Here we determined three structures of human PLCγ2 in autoinhibited states, which reveal dynamic interactions at the autoinhibition interface, involving the conformational flexibility of the Src homology 3 (SH3) domain in the inhibitory region, and its previously unknown interaction with a carboxyl-terminal helical domain in the core region. We also determined a structure of PLCγ2 bound to the kinase domain of fibroblast growth factor receptor 1 (FGFR1), which demonstrates the recognition of FGFR1 by the nSH2 domain in the inhibitory region of PLCγ2. Our results provide structural insights into PLCγ2 regulation that will facilitate future mechanistic studies to understand the entire activation process. Show less

Infigratinib, an FGFR1-3 selective oral tyrosine kinase inhibitor, has shown clinical activity in cancers with FGFR alterations. The pharmacokinetics (PK) of infigratinib and its major metabolites have been characterized in global populations. This study examined the PK profile of infigratinib and its metabolites in Chinese patients. In this phase II, open-label, single-arm study in China, patients with advanced gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJ) harboring FGFR2 gene amplification received 125 mg infigratinib orally once daily in a "3 weeks on, 1 week off" schedule for 28-day cycles. Plasma PK parameters were calculated with a non-compartmental model. Data were available from 21 patients (19 GC and two GEJ). After a single dose, peak infigratinib plasma concentration was reached at a median time of 3.1 h, with geometric mean C Show less

BRAF and MEK inhibitors are standard treatments in histiocytic disorders, such as Erdheim-Chester disease (ECD). Some patients lack MAPK-pathway alterations, making these treatments less effective. We describe three patients with histiocytic disorders who have novel non-MAPK pathway alterations. These alterations were studied through genomic and in silico analyses when applicable, then treated with off-label medications rationally selected on the basis of genomic alterations. Patient 1 had rapidly progressive ECD involving the CNS. A CSF1R in-frame deletion (p.S560_P566del) was identified, and in silico modeling predicted a gain-of-function mutation. This alteration was targeted with pexidartinib, which led to a clinical complete response (CR) within 2 months, and a partial response (PR) on imaging after 3 months. After 15 months, the disease became resistant to pexidartinib and transformed to histiocytic sarcoma. Patient 2 has skin-only involvement of a xanthogranuloma disorder. A KIF5B-FGFR1 fusion was identified on RNA sequencing and targeted with pemigatinib. At 24 months of follow-up, she remains in a clinical PR. Patient 3 has ECD involving the bone marrow, gastrointestinal tract, and subcutaneous tissues. A MEF2C-FLT3 fusion was identified and targeted with sorafenib. He achieved a clinical CR and radiographic PR within 3 months, which has continued for 30 months. We report three patients with histiocytic disorders harboring novel alterations who had sustained responses to off-label kinase inhibitors specific to their histiocytic disorder. Pathogenic variants outside of the MAPK pathway, including variants of unknown significant, may be targeted with readily available small molecules. Show less

Colorectal cancer contributes to cancer-related deaths and health disparities in the Hispanic and Latino community. To probe both the biological and genetic bases of the disparities, we characterized features of colorectal cancer in terms of somatic alterations and genetic similarity. Specifically, we conducted a comprehensive genome-scale analysis of 67 Hispanic and Latino samples. We performed DNA exome sequencing for somatic mutations, somatic copy number alterations, and genetic similarity. We also performed RNA sequencing for differential gene expression, cellular pathways, and gene fusions. We analyzed all samples for 22 important CRC gene mutations, 8 gene amplifications, and 25 CRC gene fusions. Then, we compared our data from the Hispanic and Latino samples to publicly available, Non-Hispanic White (NHW) cohorts. According to our analyses, twenty-four percent of colorectal carcinomas were hypermutated when patients were of Peruvians-from-Lima-like (1KG-PEL-like) genetic similarity population from the 1000 genome project. Moreover, most of these cases occurred in patients who were less than fiay years old age at diagnosis. Excluding hypermutated tumors, approximately 55% of colon cancers and 58% of rectum cancers exhibited two similar features: 1) the paderns of genomic alterations; 2) percentage of 1KG-PEL-like. We analyzed all samples -- which had a median 1KG-PEL-like proportion of 55% -- for 22 important CRC gene mutations, 8 gene amplifications, and 25 CRC gene fusions. One notable example of a frequently observed gene mutation was SMAD4. Samples with SMAD4 alterations, which are known to support tumor growth and progression, had the highest 1KG-PEL-like proportion (63%). According to our results from risk association analyses and differential gene expression, SMAD4 alterations were significant when we compared Hispanic and Latino samples to NHW cohorts. Of the 8 drug-targetable amplifications, PIK3CA and PI3K exhibited an average 1KG-PEL-like of over 55%. Of the 25 relevant CRC gene fusions, targetable genes included ALK, FGFR1, RAF1, and PTPRK; PTPRK was observed in a sample with the highest 1KG-PEL-like proportion (95%). Using Integrative analysis, we also detected recurrent alterations in the WNT, TGFB, TP53, IGF2/PI3K, and RTK/RAS pathways. Importantly, these alterations mostly occurred in young patients with high 1KG-PEL-like. These findings highlight the potential for tailoring precision medicine therapeutics to an underrepresented population. Our study advances the molecular profiling of CRC in Hispanics and Latinos. In toto, genetic similarity appears to be an important component in understanding colorectal carcinogenesis and has the potential to advance cancer health disparities research. Show less

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, Show less

FGFR1 is a key member of the fibroblast growth factor receptor family, mediating critical signaling pathways such as RAS-MAPK and PI3K-AKT. which are integral to regulating essential cellular processes, including proliferation, differentiation, and survival. Alterations in FGFR1 can lead to constitutive activation of signaling pathways that drive oncogenesis by promoting uncontrolled cell division, inhibiting apoptosis, and enhancing the metastatic potential of cancer cells. This article reviews the activation mechanisms and signaling pathways of FGFR1 and provides a detailed exposition of the types of FGFR1 aberration. Furthermore, we have compiled a comprehensive overview of current therapies targeting FGFR1 aberration in cancer, aiming to offer new perspectives for future cancer treatments by focusing on drugs that address specific FGFR1 alterations. Show less

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with a median overall survival (OS) of 15-18 months despite standard treatments. Approximately 8% of GBM cases exhibit genomic alterations in fibroblast growth factor receptors (FGFRs), particularly FGFR1 and FGFR3. Next-generation sequencing techniques have identified various FGFR3 fusions in GBM. This report presents a novel FGFR3 fusion with fatty acid synthase (FASN) in a 41-year-old male diagnosed with GBM. The patient presented with a persistent headache, and imaging revealed a right frontal lobe lesion. Surgical resection and subsequent histopathology confirmed GBM. Initial NGS analysis showed no mutations in the IDH1, IDH2 or H3F3 genes, but revealed a TERT promoter mutation and CDKN2A/2B and PTEN deletions. Postoperative treatment included radiotherapy and temozolomide. Despite initial management, recurrence occurred four months post-diagnosis, confirmed by MRI and histology. A second surgery identified a novel FGFR3-FASN fusion, alongside increased Ki67 expression. The recurrence was managed with regorafenib and bevacizumab, though complications like hand-foot syndrome and radiation necrosis arose. Despite initial improvement, the patient died 15 months after diagnosis. This case underscores the importance of understanding GBM's molecular landscape for effective treatment strategies. The novel FGFR3-FASN fusion suggests potential implications for GBM recurrence and lipid metabolism. Further studies are warranted to explore FGFR3-FASN's role in GBM and its therapeutic targeting. Show less

Next-generation sequencing (NGS) has been offered as a large-scale and effective genomic analyzing tool. In this research, we seek to examine the possible benefits of an actionable mutation panel in association with clinical and pathological features in the treatment of esophageal cancer. In our study, 85 cases whose diagnosis of carcinoma was confirmed histopathologically either by endoscopic biopsy or esophageal surgery between 2010 and 2020 were identified from the hospital database. In formalin-fixed, paraffin-embedded tumor samples, a total of 20 genes of AKT1, ALK, BRAF, DDR, EGFR, ERBB2, ERBB3, ESR1, FGFR1, KIT, KRAS, MAP2K1, MET, NRAS, NTRK, PDGFRA, PIK3CA, PTEN, RICTOR and ROS1 were analyzed via NGS for actionable mutations. Of 85 cases, 47 patients (55.3%) were men and 38 (44.7%) were women, and the mean age of the patients was 58.01±11.45 years. There were substantial distinctions in the variables of pathogenicity of variant, operation type, stage, and both lymphovascular and perineural invasion (p<0.05). Most of the primary tumors were situated in the lower thoracic esophagus (n=23; 27%). PIK3CA variant was the highest in number among the variant types (n=17) and was detected in 41.2% of the lower thoracic tumors. The increases in mutation numbers of >2 were especially concentrated in the lower thoracic esophageal carcinomas. The utility of an actionable multigene panel revealed the value of a well-designed NGS workflow in the practical use of clinical outcomes via the prediction of responsiveness to therapeutic agents or indications for novel treatment modalities in addition to the estimation of prognosis. Show less

Lung cancer, a common type of malignant neoplasm, has seen significant advancements in the treatment of lung adenocarcinoma (LUAD). However, the management of lung squamous cell carcinoma (LSCC) continues to pose challenges. Traditional treatment methods for LSCC encompass surgical resection, chemotherapy, and radiotherapy. The introduction of targeted therapy and immunotherapy has greatly benefited LSCC patients, but issues such as limited immune response rates and adverse reactions persist. Therefore, gaining a deeper comprehension of the underlying mechanisms holds immense importance. This review provides an in-depth overview of classical signaling pathways and therapeutic targets, including the PI3K signaling pathway, CDK4/6 pathway, FGFR1 pathway and EGFR pathway. Additionally, we delve into alternative signaling pathways and potential targets that could offer new therapeutic avenues for LSCC. Lastly, we summarize the latest advancements in targeted therapy combined with immune checkpoint blockade (ICB) therapy for LSCC and discuss the prospects and challenges in this field. Show less