Fibroblast Growth Factor Receptor Gene Research Articles

Landscape of fibroblast growth factor receptor (FGFR) genomic alterations (GA) in urothelial bladder cancer (UBC).

4568 Background: Urothelial bladder carcinomas (UBC) with genomic alterations (GA) in the Fibroblast Growth Factor Receptor ( FGFR) genes have been postulated to be less responsive to immune checkpoint inhibitors (ICI). Immune microenvironment of these tumors could be altered due to suppression of interferon signaling pathways. Here, we present comprehensive genomic profiling (CGP) of FGFR altered UBC to study the underlying immunogenomic mechanisms of response and resistance. Methods: 4,035 UBC underwent hybrid capture based CGP. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined using 114 loci. Programmed death ligand (PD-L1) expression in tumor cells was assessed by IHC (Dako 22C3). Results: 894 (22%) of UBC featured FGFR GA ( FGFR1 3.7%; FGFR2 1.1%; FGFR3 17.4%). Gender and age distribution was similar in all groups. FGFR3 cases had lower GA/tumor and 14.7% GA were fusions. ERBB2 amplification was significantly higher in FGFR1/2 altered UBC compared with FGFR3 altered UBC. MTOR pathway GA were highest in FGFR3 altered UBC. FGFR3 altered UBC featured significantly higher frequencies of biomarkers predicting resistance to ICI including lower TMB, lower PD-L1 expression and higher frequencies of GA in MDM2. FGFR3 driven UBC also features significantly higher frequencies of CDKN2A/B loss and MTAP loss which have also recently been linked to IO drug resistance. Conclusions: UBC harboring FGFR GA have increased frequency of alterations that have been linked to ICI resistance. Further evaluation of FGFR-based biomarkers in UBC clinical trials focused on the assessment of the patient response to ICI appears warranted. [Table: see text]

Image-based detection of FGFR3-fusion in urothelial bladder cancer.

3072 Background: Fibroblast growth factor receptor-3 (FGFR3) is a transmembrane protein, somatically altered in a large spectrum of cancer types. Chromosomal rearrangement resulting in FGFR3 gene fusions leads to a constitutively active tyrosine kinase, mediating tumorigenesis. FGFR3-fusion is a prognostic and predictive marker as well as a validated therapeutic target in urothelial bladder cancer. Both FISH and RT-PCR assays can be used for the detection of FGFR3 rearrangements while immunohistochemistry lacks sufficient sensitivity and specificity. In recent years advances in next-generation sequencing improved their ability to detect these alterations in clinical settings. However, systemic screening of these alterations is still expensive, time-consuming, and requires expertise personnel for data analysis and interpretation. In this study, we aimed to develop and validate an alternative machine learning (ML) based method for the detection of FGFR3-fusions directly from routine pathology hematoxylin and eosin (H&E) slides. Methods: A cohort of 388 H&E whole slide images of bladder urothelial carcinoma samples, obtained from the TCGA Research Network ( https://www.cancer.gov/tcga ) was used. Cases were randomly divided into training (n = 238) and testing (n = 150) sets. Advanced Convolutional Neural Network (CNN) was used to generate the FGFR3-fusion classifier on the training set following validation on the testing set. Results: Validation of the FGFR3-fusion classifier was performed on a cohort of 150 cases from 19 different centers, including three positive cases of FGFR3-TACC3 fusions and 147 negative cases. The AI-classifier performance was measured in comparison to the TCGA dataset. The model demonstrated 100% sensitivity and 94% specificity, with an Area Under the Curve (AUC) of 0.96. Conclusions: Herein, we demonstrate a real-time ML-based genomic testing solution for FGFR3-fusion detection in bladder cancer directly from H&E stained slide images. Utilization of such an alternative method can facilitate fast, accurate, and systemic screening of patients if integrated within the routine pathological pipeline supporting targeted therapy treatment for these patients.

Screening of FGFR patients for FGFR directed clinical trials in Network Genomic Medicine (NGM): Real-world data.

e21013 Background: The fibroblast growth factor receptor (FGFR) 1-4 genes show a heterogenic landscape of alterations in non-small cell lung cancer (NSCLC) whereas only a small amount is yet considered to have oncogenic potential. The frequency of activating FGFR alterations is low, counting for approximately 2% of NSCLC. We have screened NSCLC patients (pts) for FGFR translocations/mutations within NGM and analysed them on FGFR alteration frequency, patient characteristics and outcome. Methods: From 04/2019 to 01/2020 we screened 472 squamous NSCLC for FGFR gene alterations and from 02/2020 to 12/2021 an additional 5286 patients including all NSCLC cases. Of these 5286 pts, 1097 pts were analysed for FGFR fusions. We used DNA-NGS for FGFR-mutations and RNA-NGS for FGFR–translocations. Activating mutations were defined according to the publicly available molecular data bases and published data. Results: Within the cohort of 5758 NSCLC patients, we found 316 (5.5%) patients with FGFR alterations. Sixty-six (20.9% of FGFR, 1.1% of NSCLC) patients had alterations classified as activating, of whom 39 had FGFR point mutations and 27 FGFR translocations. Concerning the patients with activating alterations, they had UICC stage III or IV at time of diagnosis; 22 were females; 58 patients had squamous cell carcinoma, 6 patients had adenocarcinoma and 2 had large cell neuroendocrine carcinoma. Fifty-three patients (80.3%) with activating FGFR alteration had a co-mutation: TP53 (inactivating) co-mutation was seen in 41 cases (62.1%) and 19 cases had either PTEN (7 pts), KRAS (4), EGFR (3), PIK3CA (2), ROS1 (1), ALK (1) or BRAF (1) mutations. Ten patients were included in a FGFR-targeted trial. Sixty patients were available for follow-up. The median overall survival (mOS) was 21.4 month (95%CI: 16.8–25.9) for all patients with activating FGFR alteration, whereas mOS was 18.5 month (95%CI: 13.2-23.9) for FGFR mutation and 25.3 months (95%CI: 17.8-32.9) for FGFR fusions. Conclusions: FGFR 1-4 gene alterations are rare. Large molecular and clinical networks are necessary to identify these pts. Prognostic factors of FGFR patients are currently not defined. Further assessments on molecular and clinical features in FGFR altered NSCLC are needed to identify sensitivity to FGFR inhibition. Clinical trials with specific FGFR inhibitors are ongoing.

Clinical features and FGFR3 mutations of children with achondroplasia

To study the clinical features and fibroblast growth factor receptor 3 (FGFR3) gene mutations of children with achondroplasia (ACH) through an analysis of 17 cases. A retrospective analysis was performed on the clinical data and FGFR3 gene detection results of 17 children with ACH who were diagnosed from January 2009 to October 2021. Of the 17 children with ACH, common clinical manifestations included disproportionate short stature (100%, 17/17), macrocephaly (100%, 17/17), trident hand (82%, 14/17), and genu varum (88%, 15/17). The common imaging findings were rhizomelic shortening of the long bones (100%, 17/17) and narrowing of the lumbar intervertebral space (88%, 15/17). Major complications included skeletal dysplasia (100%, 17/17), middle ear dysfunction (82%, 14/17), motor/language developmental delay (88%, 15/17), chronic pain (59%, 10/17), sleep apnea (53%, 9/17), obesity (41%, 7/17), foramen magnum stenosis (35%, 6/17), and hydrocephalus (24%, 4/17). All 17 children (100%) had FGFR3 mutations, among whom 13 had c.1138G>A hotspot mutations of the FGFR3 gene, 2 had c.1138G>C mutations of the FGFR3 gene, and 2 had unreported mutations, with c.1252C>T mutations of the FGFR3 gene in one child and c.445+2_445+5delTAGG mutations of the FGFR3 gene in the other child. This study identifies the unreported mutation sites of the FGFR3 gene, which extends the gene mutation spectrum of ACH. ACH is a progressive disease requiring lifelong management through multidisciplinary collaboration.

Abstract P5-08-12: Efficacy of futibatinib, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in breast cancer models with FGFR alterations

Abstract Purpose: Several FGFR alterations have been found in breast cancer, however, their role as a therapeutic target in breast has been controversial. Futibatinib (TAS-120; Taiho) is a novel, selective pan-FGFR inhibitor which irreversibly binds to and inhibits FGFR1-4 at nanomolar concentrations. We sought to determine the efficacy of futibatinib in breast cancer models with differing FGFR alterations. Experimental Design: In vivo, antitumor efficacy was evaluated by tumor growth curves and event-free survival in a panel of patient-derived xenografts (PDXs) from breast cancer patients with different FGFR1-4 alterations. Genomic alterations in the PDXs were characterized by next generation sequencing. Correlation of FGFR gene expression in matched patient tumors and PDXs was analyzed by RNA sequencing. In vitro, FGFR2 Y375C mutant and FGFR2-BICC1 fusion expressing MCF10A cell lines were generated, and effect on cell proliferation, colony formation assay, and cell signaling was assessed with and without futibatinib. Frequency of FGFR mutations and FGFR2 amplification was compiled from internal and public databases. Results: Breast cancer PDXs varied in their expression of FGFR1-4. FGFR gene expression significantly correlated between matched patient tumors and PDXs derived from them, however, PDXs had higher levels of FGFR3 and FGFR4 expression compared to patient samples. Futibatinib inhibited tumor growth in three of 10 PDX models, with tumor stabilization in a FGFR2 amplified model and prolonged tumor regression (more than 110 days) in a PDX bearing a FGFR2 Y375C mutation. In vitro, expression of FGFR2 Y375C, as well as FGFR2-BICC fusion in normal-like MCF10A cells enhanced growth, colony formation ability and FGFR signaling. Cells expressing FGFR2 Y375C as well as FGFR2-BICC fusions were more sensitive to futibatinib. In the five breast cancer genomic series we analyzed, FGFR2 mutations and amplifications were found in 1.1%-2.6% and 1.4%-2.5%, respectively. Conclusions: Futibatinib had single agent activity of selected breast cancer PDX models. FGFR2 activating mutations and amplification may represent rare but promising therapeutic targets to FGFR inhibition. Citation Format: Turcin Saridogan, Argun Akcakanat, Ming Zhao, Kurt W. Evans, Erkan Yuca, Stephen Scott, Bryce P. Kirby, Xiaofeng Zheng, Senthil Damodaran, Funda Meric-Bernstam. Efficacy of futibatinib, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in breast cancer models with FGFR alterations [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-12.

ACT-1 Multicenter investigator-initiated registration-directed Phase 2 study of E7090 in subjects with advanced or recurrent solid tumors with fibroblast growth factor receptor (FGFR) gene alteration: FORTUNE trial

Background: Genetic alterations of FGFRs are known to play an important role in the proliferation, survival, and migration of cancer cells as well as tumor angiogenesis and drug resistance. E7090 is an orally available selective tyrosine kinase inhibitor for FGFR1-3. A global Phase 2 study of E7090 in subjects with unresectable advanced or metastatic cholangiocarcinoma harboring FGFR2 gene fusion is ongoing (NCT04238715). We recently reported FGFR alterations that are highly sensitive to E7090 using a high-throughput functional evaluation method called MANO method (Nakamura et al. npj Precision Oncology, 2021), narrowing down the most promising FGFR alteration targets. Here, we designed a single-arm, open-label, investigator-initiated multicenter Phase 2 basket study to evaluate the efficacy and safety of E7090 in subjects with advanced or recurrent solid tumors harboring FGFR gene alterations, focusing on alterations identified by MANO method, as a sub-study under the nationwide large registry for rare cancers in Japan (MASTER KEY Project). Methods: The key eligibility criteria are: 1) Histologically confirmed metastatic or locally advanced solid tumor; 2) Ineffective to or intolerant to first line treatment, or for which standard treatment is no longer available; and 3) Confirmed FGFR gene alterations via next-generation sequencing assays that are reimbursed by insurance. Subjects will receive E7090 140 mg orally once daily until disease progression or development of unacceptable toxicity. The primary endpoint is objective response rate (ORR) by independent central review (RECIST v1.1), and the secondary endpoints include ORR by investigator assessment, progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. For primary brain tumors, RANO criteria is also applied in assessment of response. The study enrolls approximately 45 subjects. (Clinical Trial Registry: jRCT2031210043, ClinicalTrials.gov: NCT04962867)

Female infant with apert syndrome and high imperforate anus without fistula

Apert syndrome (AS) is a rare type of congenital craniofacial dysmorphic and severe syndactyly of the hands and feet. Fibroblast growth factor receptor (FGFR) gene mutations are suspect to be involved in this anomaly. The distinct features are craniosynostosis-a condition of premature closure of skull's sutures-, midface hypoplasia-an incomplete development of the middle of the face-, and syndactyly-webbed fingers or toes-. The anorectal malformations (ARMs) associations with AS is rare, and the genetic link is highly complex. Only 12.7% of ARMs cases were associated with a syndrome that has a well-known impact on intellectual development, including AS. To our knowledge, this is the first reported case of AS with a high imperforate anus without fistula. • The association of anorectal malformations (ARMs) with AS is rare, and the genetic link is highly complex. • High imperforate anus can be associated with apert syndrome. This is the first reported case of apert syndrome and high imperforate anus.

"Association of Fibroblast Growth Factor Receptor Gene (FGFR2) Polymorphism (rs2981582) and its Expression with Breast Cancer"

Lucy Chawisangzeli1, Sameer Ahmad Guru*2, Binita Goswami3, Meeta Singh4, Pawanindra Lal5 and BC Koner6 Author Affiliations 1Resident, Department of Biochemistry, Maulana Azad Medical College, India 2Postdoctoral Associate, Lurie Children’s Hospital, Northwestern University, USA 3Professor, Department of Biochemistry, Maulana Azad Medical College, India 4Associate Professor, Department of Pathology, Maulana Azad Medical College, India 5Director Professor, Department of Surgery, Maulana Azad Medical College, India 6Director professor & Head, Department of Biochemistry, Maulana Azad Medical College, India Received: October 27, 2021 | Published: November 05, 2021 Corresponding author: Sameer Ahmad Guru, Postdoctral Associate, Developmental Systems Biology, Ann and Lurie Childens Hospital, Northwestern University, Chicago DOI: 10.26717/BJSTR.2021.39.006353

Detection of fibroblast growth factor receptor 3 (FGFR3) gene polymorphism in multiple myeloma patients in Baghdad and Babylon provinces

Human myeloma is often used to depict primary myeloma cells since it does not completely capture patient variability. The majority of its genetic history is unclear. Fibroblast Growth Factor Receptor (FGFR) is one of four highly-conserved cell-membrane-related FGFR1-4 systems that are involved in embryo-growth, development, cell proliferation, and angiogenesis in the signaling processes. This study aimed to investigate FGFR3 polymorphisms using PCR-SSCP analysis in 40 patients and healthy persons as control for myeloma cancer. PCR approach was used for screening FGFR3, followed by single strand conformation polymorphism (SSCP), which show that the FGFR3 variations of the gene polymorphism might be affected by myeloma susceptibility. The results showed possibility to detect Multiplemyeloma by the variations of FGFR3 gene polymorphisms.

High-Resolution Melting Analysis for Rapid Detection of Mutations in Patients with FGFR3-Related Skeletal Dysplasias.

Background: Mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are related to skeletal dysplasias (SDs): acondroplasia (ACH), hypochodroplasia (HCH) and type I (TDI) and II (TDII) tanatophoric dysplasias. This study was designed to standardize and implement a high-resolution melting (HRM) technique to identify mutations in patients with these phenotypes. Methods: Initially, FGFR3 gene segments from 84 patients were PCR amplified and subjected to Sanger sequencing. Samples from 29 patients positive for mutations were analyzed by HRM. Results: Twelve of the patients FGFR3 mutations had ACH (six g.16081 G > A, three g.16081 G > C and three g.16081 G > A + g.16002 C > T); thirteen of patients with HCH had FGFR3 mutations (eight g.17333 C > A, five g.17333 C > G and five were negative); and four patients with DTI had FGFR3 mutations (three g.13526 C > T and one g.16051G > T and two patients with DTII (presented mutation g.17852 A > G). When analyzing the four SDs altogether, an overlap of the dissociation curves was observed, making genotyping difficult. When analyzed separately, however, the HRM analysis method proved to be efficient for discriminating among the mutations for each SD type, except for those patients carrying additional polymorphism concomitant to the recurrent mutation. Conclusion: We conclude that for recurrent mutations in the FGFR3 gene, that the HRM technique can be used as a faster, reliable and less expensive genotyping routine for the diagnosis of these pathologies than Sanger sequencing.

Apert's Syndrome: A Rare Congenital Disorder

Apert's syndrome (acrocephalosyndactyly) is a developmental malformation characterized by craniosynostosis, syndactyly, and dysmorphic facial features. The purpose of this paper is to report a case of an 8-year-old child affected with Apert's syndrome with emphasis on the craniofacial and oral features. It demonstrates autosomal dominant inheritance and occurs due to point mutation of fibroblast growth factor receptor-2 gene in chromosome 10q25 and 10q26. The patient presented with brachydactyly, syndactyly, polydactyly, hypoplastic maxilla, and malalignment of teeth. The cases of Apert's syndrome can only be treated by multidisciplinary approach. Early diagnosis and proper counseling of families can help in better management.

SHP2 as a Potential Therapeutic Target in Diffuse-Type Gastric Carcinoma Addicted to Receptor Tyrosine Kinase Signaling.

Simple SummaryDiffuse-type gastric carcinoma (DGC) is characterized by rapid infiltrative growth associated with massive stroma and frequent peritoneal dissemination, which leads to poor patient outcomes. In this study, we found that the oncogenic tyrosine phosphatase SHP2 is tyrosine-phosphorylated downstream of the amplified receptor tyrosine kinases (RTKs) Met and fibroblast growth factor receptor 2 (FGFR2) in DGC cell lines. SHP2 knockdown or pharmacological inhibition selectively suppressed the growth of DGC addicted to amplified Met and FGFR2. Moreover, targeting SHP2 abrogated malignant phenotypes, including peritoneal dissemination, of Met-addicted DGC and could overcome acquired resistance to Met inhibitors. Our findings suggest that SHP2 is a potential target for the treatment of DGC addicted to amplified RTK signaling.Diffuse-type gastric carcinoma (DGC) exhibits aggressive progression associated with rapid infiltrative growth, massive fibrosis, and peritoneal dissemination. Gene amplification of Met and fibroblast growth factor receptor 2 (FGFR2) receptor tyrosine kinases (RTKs) has been observed in DGC. However, the signaling pathways that promote DGC progression downstream of these RTKs remain to be fully elucidated. We previously identified an oncogenic tyrosine phosphatase, SHP2, using phospho-proteomic analysis of DGC cells with Met gene amplification. In this study, we characterized SHP2 in the progression of DGC and assessed the therapeutic potential of targeting SHP2. Although SHP2 was expressed in all gastric carcinoma cell lines examined, its tyrosine phosphorylation preferentially occurred in several DGC cell lines with Met or FGFR2 gene amplification. Met or FGFR inhibitor treatment or knockdown markedly reduced SHP2 tyrosine phosphorylation. Knockdown or pharmacological inhibition of SHP2 selectively suppressed the growth of DGC cells addicted to Met or FGFR2, even when they acquired resistance to Met inhibitors. Moreover, SHP2 knockdown or pharmacological inhibition blocked the migration and invasion of Met-addicted DGC cells in vitro and their peritoneal dissemination in a mouse xenograft model. These results indicate that SHP2 is a critical regulator of the malignant progression of RTK-addicted DGC and may be a therapeutic target.

Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer

Various genetic alterations of the fibroblast growth factor receptor (FGFR) family have been detected across a wide range of cancers. However, inhibition of FGFR signaling by kinase inhibitors demonstrated limited clinical effectiveness. Herein, we evaluated the transforming activity and sensitivity of 160 nonsynonymous FGFR mutations and ten fusion genes to seven FGFR tyrosine kinase inhibitors (TKI) using the mixed-all-nominated-in-one (MANO) method, a high-throughput functional assay. The oncogenicity of 71 mutants was newly discovered in this study. The FGFR TKIs showed anti-proliferative activities against the wild-type FGFRs and their fusions, while several hotspot mutants were relatively resistant to those TKIs. The drug sensitivities assessed with the MANO method were well concordant with those evaluated using in vitro and in vivo assays. Comprehensive analysis of published FGFR structures revealed a possible mechanism through which oncogenic FGFR mutations reduce sensitivity to TKIs. It was further revealed that recurrent compound mutations within FGFRs affect the transforming potential and TKI-sensitivity of corresponding kinases. In conclusion, our study suggests the importance of selecting suitable inhibitors against individual FGFR variants. Moreover, it reveals the necessity to develop next-generation FGFR inhibitors, which are effective against all oncogenic FGFR variants.

Achondroplasia: Clinical, Radiological and Molecular Profile from Rare Disease Centre, India.

Achondroplasia is the most common autosomal dominant form of skeletal dysplasia and is caused by heterozygous mutations of the fibroblast growth factor receptor 3 ( FGFR3 ) gene at region 4p16.3. This study highlights the data of achondroplasia cases, clinical spectrum, and their outcome from small cities and the region around Rajasthan. The data for analysis were collected retrospectively from genetic records of rare disease clinic in Rajasthan. Clinical profile, radiographic features, molecular test results, and outcome were collected. There were 15 cases, including eight males and seven females, in this cohort. All had facial hypoplasia, depressed nasal bridge, prominent forehead, and characteristic radiographic features. A total of 14 cases were sporadic and one case was inherited from the mother. Mutation analysis showed 13 out of 15 cases with the p.Gly380Arg mutation in the FGFR3 gene. Hydrocephalus was developed in three cases, required shunting in two cases.

Abstract 353: The translocations of FGFR2 and NTRK1 in intrahepatic cholangiocarcinoma and their discordance in status by FISH and IHC

Abstract Objectives Intrahepatic cholangiocarcinoma(ICC) is a subtype of primary liver cancer lacking effective therapeutic agents. Chromosomal translocations of the neurotrophic tyrosine receptor kinase (NTRK) and fibroblast growth factor receptor 2 (FGFR2) have become promising therapeutic targets in several kinds of malignancies, but their incidence and optimum testing standards have not been fully assessed in ICC. The current study investigated the status of FGFR2 and NTRK1 genes in ICCs by different methods, and their correlation with clinicopathological features. Methods We examined FGFR2 and NTRK protein expression by immunohistochemistry (IHC), FGFR2 and NTRK1 gene translocation by fluorescence in situ hybridization (FISH). Samples were collected from 160 patients who underwent surgical resection for ICC. Break-apart probes were employed and the ratios of FGFR2 or NTRK1/chromosome enumeration probe (CEP) 10 double-color probes were determined. Furthermore, we analyzed the clinicopathological significances of the patients. Results FGFR2-positive status was detected in 13.2% of ICCs. Twenty-one patients (13.2%) were detected FGFR2 translocation. Compared with the patients with normal FGFR2, FGFR2-positivity tended to correlate with low histological grade, less mucus(P=0.024), and lower preoperative serum CA199 level, showed(P<0.01)in certain tumors, and were accompanied by hepatitis B virus infection more frequently (P<0.01). Histologically, tumors with FGFR2 translocation had a tendency to manifest small-duct subtype. The Kaplan-Meier survival analysis showed that patients with FGFR2 translocation had better prognosis in 5-year survival than those with normal FGFR2 (P=0.007),( median overall survival, 57 months vs 33 months). With regard to the NTRK1 translocated ICCs, 5.6% (9/160) were detected to have NTRK1 translocation, 5 cases were female, 4 were with hepatitis B virus infection, and 6 showed histologically large-duct subtype. Interestingly, two patients demonstrated both FGFR2 and NTRK1 translocation by FISH. However, among the 9 cases with NTRK1 translocation, only 2 cases showed moderately positive on IHC, with the remaining 7 cases weak or negative. Similarly, only 14.3% (3/21) FGFR2 translocation FISH-positive cases showed moderate to strong positive by IHC. Concordance rates between IHC and FISH were 22.2% for NTRK1 and 14.3% for FGFR2. The positive rate by IHC is significantly lower than that by FISH on both NTRK1 (2.5% vs 5%) and FGFR2 (3.7% vs 13%) according to our cohort. Conclusions The positive rate by IHC is significantly lower than that by FISH on both genes. The findings of this study suggest that a large subgroup of FGFR2-positive and NTRK-positive cases can be considered for targeted therapy. Moreover, the FGFR2 and NTRK status in ICCs should be determined carefully using a sensitive approach toward larger cancer tissues. Citation Format: Yining Zou, Yuan Ji. The translocations of FGFR2 and NTRK1 in intrahepatic cholangiocarcinoma and their discordance in status by FISH and IHC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 353.

Fibroblast Growth Factor Receptor 3 (FGFR3) Gene Amplification in Patients with Urothelial Carcinoma of the Urinary Bladder

Background: The fibroblast growth factor receptors (FGFRs) family includes five tyrosine kinase receptors, which play an important role in many cellular mechanisms including proliferation, migration and survival. Deregulations in the genes that coding for these receptors, mainly the FGFR3 gene, had been reported in patients with urothelial carcinoma of the urinary bladder. Objective: To estimate the frequency of FGFR3 gene amplification in patients with urothelial carcinoma of the urinary bladder and its relation to some clinico-pathological parameters of the tumor. Methods: The present retrospective study included 30 paraffin blocks of urothelial carcinoma tissue (trans-urethral resection of bladder tumor (TURBT)), and 10 samples of normal bladder tissue (control group). Sections were taken from each paraffin block for studying FGFR3 gene amplification by fluorescent in situ hybridization (FISH) technique. Results: FGFR3 gene was shown to be amplified in 4 (13.3%) out of 30 urothelial carcinoma cases. There was significant relation between FGFR3 gene amplification and tumor’s pathological stage (p=0.037). FGFR3 gene wasn’t statistically correlated with the patient’s age, gender, tumor’s grade or the lympho-vascular permeation. Conclusion: FGFR3 gene amplification was detected in 13.3% of urothelial carcinoma of the urinary bladder cases, which may reflect its role in carcinogenesis process. This amplification was statically correlated to tumor’s pathological stage suggesting its relation to tumor progression. Keywords: FGFR3, FISH, TURBT, urothelial carcinoma, gene amplification Citation: Al-Marashi MA, Qasim BJ. Fibroblast Growth Factor Receptor 3 (FGFR3) gene amplification in patients with urothelial carcinoma of the urinary bladder.Iraqi JMS. 2021; 19(1): 116-125. doi: 10.22578/IJMS.19.1.15

Medical therapies for intra-hepatic cholangiocarcinoma

Medical therapies for intra-hepatic cholangiocarcinoma

Apert Syndrome: A Rare Genetic Disorder

Apert syndrome is a rare type I acrocephalosyndactyly syndrome having autosomal dominant inheritance due to mutations in the fibroblast growth factor receptors gene. New or fresh mutations are also frequent. It is characterized by dysmorphic face, craniosynostosis, severe syndactyly of the hands and feet. Apert syndrome affects the first branchial or pharyngeal arch, the precursor of the maxilla and mandible. Disturbances in the development of branchial arches during fetal period create extensive malformation in different parts of the body. Management of Apert syndrome requires a multidisciplinary approach. We, hereby, report a case of a 45-days old baby with Apert syndrome.
 Northern International Medical College Journal Vol.11 (2) Jan 2020: 475-477

Using deep learning to identify bladder cancers with FGFR-activating mutations from histology images.

BackgroundIn recent years, the fibroblast growth factor receptor (FGFR) pathway has been proven to be an important therapeutic target in bladder cancer. FGFR‐targeted therapies are effective for patients with FGFR mutation, which can be discovered through genetic sequencing. However, genetic sequencing is not commonly performed at diagnosis, whereas a histologic assessment of the tumor is. We aim to computationally extract imaging biomarkers from existing tumor diagnostic slides in order to predict FGFR alterations in bladder cancer.MethodsThis study analyzed genomic profiles and H&E‐stained tumor diagnostic slides of bladder cancer cases from The Cancer Genome Atlas (n = 418 cases). A convolutional neural network (CNN) identified tumor‐infiltrating lymphocytes (TIL). The percentage of the tissue containing TIL (“TIL percentage”) was then used to predict FGFR activation status with a logistic regression model.ResultsThis predictive model could proficiently identify patients with any type of FGFR gene aberration using the CNN‐based TIL percentage (sensitivity = 0.89, specificity = 0.42, AUROC = 0.76). A similar model which focused on predicting patients with only FGFR2/FGFR3 mutation was also found to be highly sensitive, but also specific (sensitivity = 0.82, specificity = 0.85, AUROC = 0.86).ConclusionTIL percentage is a computationally derived image biomarker from routine tumor histology that can predict whether a tumor has FGFR mutations. CNNs and other digital pathology methods may complement genome sequencing and provide earlier screening options for candidates of targeted therapies.

Oncogenic FGFR Fusions Produce Centrosome and Cilia Defects by Ectopic Signaling.

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