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FGFR3; fibroblast growth factor receptor 3 (4p16.3)

Gene Summary

Gene:FGFR3; fibroblast growth factor receptor 3
Aliases: ACH, CEK2, JTK4, CD333, HSFGFR3EX
Location:4p16.3
Summary:This gene encodes a member of the fibroblast growth factor receptor (FGFR) family, with its amino acid sequence being highly conserved between members and among divergent species. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance. Mutations in this gene lead to craniosynostosis and multiple types of skeletal dysplasia. Three alternatively spliced transcript variants that encode different protein isoforms have been described. [provided by RefSeq, Jul 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:fibroblast growth factor receptor 3
HPRD
Source:NCBI
Updated:14 December, 2014

Gene
Ontology:

What does this gene/protein do?
Show (62)

Pathways:

What pathways are this gene/protein implicaed in?
- MAPK signaling pathway KEGG
- Regulation of actin cytoskeleton KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (5)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Urinary System CancersFGFR3 and Urinary System Cancers View Publications164
Bladder CancerFGFR3 and Bladder Cancer View Publications153
Multiple MyelomaFGFR3 and Multiple Myeloma View Publications122
Transitional Cell Cancer of the Renal Pelvis and UreterFGFR3 and Transitional Cell Cancer of the Renal Pelvis and Ureter View Publications42
Cervical CancerFGFR3 and Cervical Cancer View Publications5

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: FGFR3 (cancer-related)

Ryslik GA, Cheng Y, Cheung KH, et al.
A spatial simulation approach to account for protein structure when identifying non-random somatic mutations.
BMC Bioinformatics. 2014; 15:231 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Current research suggests that a small set of "driver" mutations are responsible for tumorigenesis while a larger body of "passenger" mutations occur in the tumor but do not progress the disease. Due to recent pharmacological successes in treating cancers caused by driver mutations, a variety of methodologies that attempt to identify such mutations have been developed. Based on the hypothesis that driver mutations tend to cluster in key regions of the protein, the development of cluster identification algorithms has become critical.
RESULTS: We have developed a novel methodology, SpacePAC (Spatial Protein Amino acid Clustering), that identifies mutational clustering by considering the protein tertiary structure directly in 3D space. By combining the mutational data in the Catalogue of Somatic Mutations in Cancer (COSMIC) and the spatial information in the Protein Data Bank (PDB), SpacePAC is able to identify novel mutation clusters in many proteins such as FGFR3 and CHRM2. In addition, SpacePAC is better able to localize the most significant mutational hotspots as demonstrated in the cases of BRAF and ALK. The R package is available on Bioconductor at: http://www.bioconductor.org/packages/release/bioc/html/SpacePAC.html.
CONCLUSION: SpacePAC adds a valuable tool to the identification of mutational clusters while considering protein tertiary structure.

Related: Cancer Prevention and Risk Reduction


Neuzillet Y, van Rhijn BW, Prigoda NL, et al.
FGFR3 mutations, but not FGFR3 expression and FGFR3 copy-number variations, are associated with favourable non-muscle invasive bladder cancer.
Virchows Arch. 2014; 465(2):207-13 [PubMed] Related Publications
The fibroblast growth factor receptor 3 (FGFR3) is a tyrosine kinase receptor frequently activated by point mutations in bladder cancer (BC). These mutations are associated with genetically stable, Ta and low-grade BC, representing the favourable BC pathway. Conversely, FGFR3 over-expression was recently found in 40 % of muscle invasive BC. We examined FGFR3 mutation status and protein expression in patients originally diagnosed as T1. We also investigated copy-number variations in FGFR3 as a possible alternative mechanism to activate FGFR3. We included 84 patients with T1 BC as their initial diagnosis. A uropathologist reviewed the slides for grade and (sub)stage. The FGFR3 mutation status was examined by PCR-SNaPshot and FGFR3 protein expression by standard immuno-histochemistry (FGFR3-B9). Copy-number status was determined in 69/84 cases with nine probes covering nine exons of the FGFR3 gene (MLPA). Of 27 BC with FGFR3 mutations, 26 (96 %) showed FGFR3 over-expression. Of the 57 wild-type BC, 27 (47 %) BC showed over-expression. Pathological parameters significantly differed (p < 0.01) between mutant and wild-type tumours with the FGFR3 mutation pointing to more favourable BC. However, if the BC exhibited wild-type FGFR3, FGFR3 protein status had no influence on grade and (sub)stage. We found six tumours with more than or equal to three copies of FGFR3. Only 1 of 22 wild-type tumours with over-expression of FGFR3 had more than or equal to three gene copies. In initially diagnosed T1 BC, only the FGFR3 mutation was significantly associated with favourable BC disease characteristics. In addition to almost all FGFR3 mutant BC, 47 % of wild-type BC displayed FGFR3 over-expression, suggesting an alternative mechanism to activate FGFR3. Increased FGFR3 copy number was a rare event and did not account for this mechanism. Nevertheless, FGFR3 wild-type tumours with over-expression of the protein may still represent a subset that might potentially benefit from FGFR3-targeted therapy.

Related: Bladder Cancer Bladder Cancer - Molecular Biology


Rüping K, Altendorf-Hofmann A, Chen Y, et al.
High IGF2 and FGFR3 are associated with tumour progression in undifferentiated pleomorphic sarcomas, but EGFR and FGFR3 mutations are a rare event.
J Cancer Res Clin Oncol. 2014; 140(8):1315-22 [PubMed] Related Publications
AIM: Pleomorphic undifferentiated sarcomas (formerly known as malignant fibrous histiocytomas) are recognised by the actual WHO classification as an undifferentiated, unclassifiable category of pleomorphic sarcomas which show no definable line of differentiation and are still a diagnosis of exclusion. Therefore, diagnostic, prognostic and therapeutic options of these tumours are urgently needed.
METHODS: Three hundred and twenty-seven spindle cell tumours of a German consultation and reference centre of soft tissue tumours consisting of 200 undifferentiated pleomorphic sarcomas (UPS), 45 low-grade sarcomas (10 low-grade fibromyxoid sarcomas, 32 low-grade myofibroblastic sarcomas and three myxoinflammatory fibroblastic sarcomas) and 82 tumours of the fasciitis family were revisited. The specimens were analysed immunohistochemically with distinct markers including tyrosine kinases and expression correlated with clinicopathological parameters. Additionally, mutational analysis was performed on specimens with high expression of EGFR and FGFR3.
RESULTS: At the protein level high IGF2 expression was observed in 86 %, FGFR3 (69 %), PDGFRA (62 %), PDGFRB (39 %), FGFR1 (8 %), EGFR (5 %), KDR/VEGFR2 (3 %), ALK (0 %) and high Ki67 (63 %) in UPS. High expressions of IGF2 and FGFR3 are significantly correlated with a higher grading (p = 0.023 and p = 0.016, respectively) and a high Ki67 index (p = 0.017 and p = 0.001, respectively). No mutations were found in the hot spots of tumour specimens with a high expression of EGFR gene (exons 18-21) and FGFR3 gene (exons 7, 10 and 15).
CONCLUSIONS: High expressions of IGF2 and FGFR3 are significantly associated with tumour progression, grading and Ki67 and might classify a subgroup of undifferentiated pleomorphic sarcoma. These markers might guide targeted therapies in these neoplasms.

Related: IGF2 Soft Tissue Sarcomas EGFR


Gaykalova DA, Mambo E, Choudhary A, et al.
Novel insight into mutational landscape of head and neck squamous cell carcinoma.
PLoS One. 2014; 9(3):e93102 [PubMed] Free Access to Full Article Related Publications
Development of head and neck squamous cell carcinoma (HNSCC) is characterized by accumulation of mutations in several oncogenes and tumor suppressor genes. We have formerly described the mutation pattern of HNSCC and described NOTCH signaling pathway alterations. Given the complexity of the HNSCC, here we extend the previous study to understand the overall HNSCC mutation context and to discover additional genetic alterations. We performed high depth targeted exon sequencing of 51 highly actionable cancer-related genes with a high frequency of mutation across many cancer types, including head and neck. DNA from primary tumor tissues and matched normal tissues was analyzed for 37 HNSCC patients. We identified 26 non-synonymous or stop-gained mutations targeting 11 of 51 selected genes. These genes were mutated in 17 out of 37 (46%) studied HNSCC patients. Smokers harbored 3.2-fold more mutations than non-smokers. Importantly, TP53 was mutated in 30%, NOTCH1 in 8% and FGFR3 in 5% of HNSCC. HPV negative patients harbored 4-fold more TP53 mutations than HPV positive patients. These data confirm prior reports of the HNSCC mutational profile. Additionally, we detected mutations in two new genes, CEBPA and FES, which have not been previously reported in HNSCC. These data extend the spectrum of HNSCC mutations and define novel mutation targets in HNSCC carcinogenesis, especially for smokers and HNSCC without HPV infection.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology


Rogler A, Hoja S, Giedl J, et al.
Loss of MTUS1/ATIP expression is associated with adverse outcome in advanced bladder carcinomas: data from a retrospective study.
BMC Cancer. 2014; 14:214 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Seventy percent of all bladder tumours tend to recur and need intensive surveillance, and a subset of tumours progress to muscle-invasive and metastatic disease. However, it is still difficult to find the adequate treatment for every individual patient as it is a very heterogeneous disease and reliable biomarkers are still missing. In our study we searched for new target genes in the critical chromosomal region 8p and investigated the potential tumour suppressor gene candidate MTUS1/ATIP in bladder cancer.
METHODS: MTUS1 was identified to be the most promising deleted target gene at 8p in aCGH analysis with 19 papillary bladder tumours. A correlation with bladder cancer was further validated using immunohistochemistry of 85 papillary and 236 advanced bladder tumours and in functional experiments. Kaplan-Meier analysis and multivariate Cox-regression addressed overall survival (OS) and disease-specific survival (DSS) as a function of MTUS1/ATIP expression. Bivariate correlations investigated associations between MTUS1/ATIP expression, patient characteristics and histopathology. MTUS1 expression was analysed in cell lines and overexpressed in RT112, where impact on viability, proliferation and migration was measured.
RESULTS: MTUS1 protein expression was lost in almost 50% of all papillary and advanced bladder cancers. Survival, however, was only influenced in advanced carcinomas, where loss of MTUS1 was associated with adverse OS and DSS. In this cohort, there was also a significant correlation of MTUS1 expression and histological subtype: positive expression was detected in all micropapillary tumours and aberrant nuclear staining was detected in a subset of plasmocytoid urothelial carcinomas. MTUS1 was expressed in all investigated bladder cell lines and overexpression in RT112 led to significantly decreased viability.
CONCLUSIONS: MTUS1 is a tumour suppressor gene in cultured bladder cancer cells and in advanced bladder tumours. It might represent one new target gene at chromosome 8p and can be used as an independent prognostic factor for advanced bladder cancer patients. The limitation of the study is the retrospective data analysis. Thus, findings should be validated with a prospective advanced bladder tumour cohort.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter Chromosome 8 CGH Bladder Cancer Bladder Cancer - Molecular Biology MTUS1


Parker BC, Engels M, Annala M, Zhang W
Emergence of FGFR family gene fusions as therapeutic targets in a wide spectrum of solid tumours.
J Pathol. 2014; 232(1):4-15 [PubMed] Related Publications
The emergence of fibroblast growth factor receptor (FGFR) family fusions across diverse cancers has brought attention to FGFR-derived cancer therapies. The discovery of the first recurrent FGFR fusion in glioblastoma was followed by discoveries of FGFR fusions in bladder, lung, breast, thyroid, oral, and prostate cancers. Drug targeting of FGFR fusions has shown promising results and should soon be translating into clinical trials. FGFR fusions form as a result of various mechanisms – predominantly deletion for FGFR1, translocation for FGFR2, and tandem duplication for FGFR3. The ability to exploit the unique targetability of FGFR fusions proves that FGFR-derived therapies could have a promising future in cancer therapeutics. Drug targeting of fusion genes has proven to be an extremely effective therapeutic approach for cancers such as the recurrent BCR–ABL1 fusion in chronic myeloid leukaemia. The recent discovery of recurrent FGFR family fusions in several cancer types has brought to attention the unique therapeutic potential for FGFR-positive patients. Understanding the diverse mechanisms of FGFR fusion formation and their oncogenic potential will shed light on the impact of FGFR-derived therapy in the future.

Related: Cancer Prevention and Risk Reduction FGFR1 gene FGFR2 gene Signal Transduction


Agarwal D, Pineda S, Michailidou K, et al.
FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.
Br J Cancer. 2014; 110(4):1088-100 [PubMed] Article available free on PMC after 18/02/2015 Related Publications
BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium.
METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.
RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2.
CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.

Related: Breast Cancer FGFR1 gene FGFR2 gene


Choi W, Porten S, Kim S, et al.
Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy.
Cancer Cell. 2014; 25(2):152-65 [PubMed] Article available free on PMC after 10/02/2015 Related Publications
Muscle-invasive bladder cancers (MIBCs) are biologically heterogeneous and have widely variable clinical outcomes and responses to conventional chemotherapy. We discovered three molecular subtypes of MIBC that resembled established molecular subtypes of breast cancer. Basal MIBCs shared biomarkers with basal breast cancers and were characterized by p63 activation, squamous differentiation, and more aggressive disease at presentation. Luminal MIBCs contained features of active PPARγ and estrogen receptor transcription and were enriched with activating FGFR3 mutations and potential FGFR inhibitor sensitivity. p53-like MIBCs were consistently resistant to neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy, and all chemoresistant tumors adopted a p53-like phenotype after therapy. Our observations have important implications for prognostication, the future clinical development of targeted agents, and disease management with conventional chemotherapy.

Related: Basal Cell Carcinoma Cisplatin Doxorubicin Methotrexate PPARG gene TP53 Bladder Cancer Bladder Cancer - Molecular Biology Vinblastine



Comprehensive molecular characterization of urothelial bladder carcinoma.
Nature. 2014; 507(7492):315-22 [PubMed] Article available free on PMC after 10/02/2015 Related Publications
Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.

Related: AKT1 Signal Transduction Bladder Cancer Bladder Cancer - Molecular Biology


Tanoue K, Wang Y, Ikeda M, et al.
Survivin-responsive conditionally replicating adenovirus kills rhabdomyosarcoma stem cells more efficiently than their progeny.
J Transl Med. 2014; 12:27 [PubMed] Article available free on PMC after 10/02/2015 Related Publications
BACKGROUND: Effective methods for eradicating cancer stem cells (CSCs), which are highly tumorigenic and resistant to conventional therapies, are urgently needed. Our previous studies demonstrated that survivin-responsive conditionally replicating adenoviruses regulated with multiple factors (Surv.m-CRAs), which selectively replicate in and kill a broad range of cancer-cell types, are promising anticancer agents. Here we examined the therapeutic potentials of a Surv.m-CRA against rhabdomyosarcoma stem cells (RSCs), in order to assess its clinical effectiveness and usefulness.
METHODS: Our previous study demonstrated that fibroblast growth factor receptor 3 (FGFR3) is a marker of RSCs. We examined survivin mRNA levels, survivin promoter activities, relative cytotoxicities of Surv.m-CRA in RSC-enriched (serum-minus) vs. RSC-exiguous (serum-plus) and FGFR3-positive vs. FGFR3-negative sorted rhabdomyosarcoma cells, and the in vivo therapeutic effects of Surv.m-CRAs on subcutaneous tumors in mice.
RESULTS: Both survivin mRNA levels and survivin promoter activities were significantly elevated under RSC-enriched relative to RSC-exiguous culture conditions, and the elevation was more prominent in FGFR3-positive vs. FGFR3-negative sorted cells than in RSC-enriched vs. RSC-exiguous conditions. Although Surv.m-CRA efficiently replicated and potently induced cell death in all populations of rhabdomyosarcoma cells, the cytotoxic effects were more pronounced in RSC-enriched or RSC-purified cells than in RSC-exiguous or progeny-purified cells. Injections of Surv.m-CRAs into tumor nodules generated by transplanting RSC-enriched cells induced significant death of rhabdomyosarcoma cells and regression of tumor nodules.
CONCLUSIONS: The unique therapeutic features of Surv.m-CRA, i.e., not only its therapeutic effectiveness against all cell populations but also its increased effectiveness against CSCs, suggest that Surv.m-CRA is promising anticancer agent.

Related: Rhabdomyosarcoma BIRC5


Salazar L, Kashiwada T, Krejci P, et al.
Fibroblast growth factor receptor 3 interacts with and activates TGFβ-activated kinase 1 tyrosine phosphorylation and NFκB signaling in multiple myeloma and bladder cancer.
PLoS One. 2014; 9(1):e86470 [PubMed] Article available free on PMC after 10/02/2015 Related Publications
Cancer is a major public health problem worldwide. In the United States alone, 1 in 4 deaths is due to cancer and for 2013 a total of 1,660,290 new cancer cases and 580,350 cancer-related deaths are projected. Comprehensive profiling of multiple cancer genomes has revealed a highly complex genetic landscape in which a large number of altered genes, varying from tumor to tumor, impact core biological pathways and processes. This has implications for therapeutic targeting of signaling networks in the development of treatments for specific cancers. The NFκB transcription factor is constitutively active in a number of hematologic and solid tumors, and many signaling pathways implicated in cancer are likely connected to NFκB activation. A critical mediator of NFκB activity is TGFβ-activated kinase 1 (TAK1). Here, we identify TAK1 as a novel interacting protein and target of fibroblast growth factor receptor 3 (FGFR3) tyrosine kinase activity. We further demonstrate that activating mutations in FGFR3 associated with both multiple myeloma and bladder cancer can modulate expression of genes that regulate NFκB signaling, and promote both NFκB transcriptional activity and cell adhesion in a manner dependent on TAK1 expression in both cancer cell types. Our findings suggest TAK1 as a potential therapeutic target for FGFR3-associated cancers, and other malignancies in which TAK1 contributes to constitutive NFκB activation.

Related: Apoptosis Myeloma Myeloma - Molecular Biology Signal Transduction Bladder Cancer Bladder Cancer - Molecular Biology


Pinto-Leite R, Carreira I, Melo J, et al.
Genomic characterization of three urinary bladder cancer cell lines: understanding genomic types of urinary bladder cancer.
Tumour Biol. 2014; 35(5):4599-617 [PubMed] Related Publications
Several genomic regions are frequently altered and associated with the type, stage and progression of urinary bladder cancer (UBC). We present the characterization of 5637, T24 and HT1376 UBC cell lines by karyotyping, fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH) and multiplex ligation-dependent probe amplification (MLPA) analysis. Some cytogenetic anomalies present in UBC were found in the three cell lines, such as chromosome 20 aneuploidy and the loss of 9p21. Some gene loci losses (e.g. CDKN2A) and gains (e.g. HRAS, BCL2L1 and PTPN1) were coincident across all cell lines. Although some significant heterogeneity and complexity were detected between them, their genomic profiles exhibited a similar pattern to UBC. We suggest that 5637 and HT1376 represent the E2F3/RB1 pathway due to amplification of 6p22.3, concomitant with loss of one copy of RB1 and mutation of the remaining copy. The HT1376 presented a 10q deletion involving PTEN region and no alteration of PIK3CA region which, in combination with the inactivation of TP53, bears more invasive and metastatic properties than 5637. The T24 belongs to the alternative pathway of FGFR3/CCND1 by presenting mutated HRAS and over-represented CCND1. These cell lines cover the more frequent subtypes of UBC and are reliable models that can be used, as a group, in preclinical studies.

Related: Apoptosis CGH FISH Bladder Cancer Bladder Cancer - Molecular Biology


Jiang H, Qu L, Wang Y, et al.
miR-99a promotes proliferation targeting FGFR3 in human epithelial ovarian cancer cells.
Biomed Pharmacother. 2014; 68(2):163-9 [PubMed] Related Publications
MiRNAs have been reported as important regulators in normal physiological processes, human cancer, and even their roles as therapeutic targets have been proposed. In epithelial ovarian cancer (EOC), the expression of miRNAs is reported to remarkably deregulate, showing that miRNAs are involved in the initiation and progression of this disease. In this study, we found that miR-99a was obviously decreased in EOC tissues, serums and cell lines SKOV-3. Importantly, fibroblast growth factor receptor 3 (FGFR3), predicted to be one target gene of miR-99a using computational algorithms, was higher in expression in EOC cells. Subsequently, FGFR3 was proved to be direct target of miR-99a by dual luciferase assay. Furthermore, overexpression of miR-99a dramatically suppressed expression level of FGFR3 at both mRNA and protein levels, proving FGFR3 to be inversely correlated with miR-99a. Finally, overexpression of miR-99a could significantly inhibit EOC cell proliferation in vitro by decreasing the expression of FGFR3 which also reduced the EOC cell growth after siRNA knockdown. Conclusively, miR-99a expression was remarkably downregulated in serums, tissues and cell and suppresses EOC cell proliferation by targeting FGFR3, suggesting miR-99a as a prospective prognosis marker and potential tumor suppressor for EOC therapeutics.

Related: Ovarian Cancer


Shinmura K, Kato H, Matsuura S, et al.
A novel somatic FGFR3 mutation in primary lung cancer.
Oncol Rep. 2014; 31(3):1219-24 [PubMed] Related Publications
The recent discovery of mutations and fusions of oncokinase genes in a subset of lung cancers (LCs) is of considerable clinical interest, since LCs containing such mutations or fusion transcripts are reportedly sensitive to kinase inhibitors. To better understand the role of the recently identified fibroblast growth factor receptor 3 (FGFR3) mutations and fusions in pulmonary carcinogenesis, we examined 214 LCs for mutations in the mutation cluster region of the FGFR3 gene using sequencing analysis. We also examined 190 LCs for the FGFR3-TACC3 and FGFR3-BAIAP2L1 fusion transcripts using reverse transcription-polymerase chain reaction (RT-PCR) analysis. Although the expression of FGFR3-TACC3 and FGFR3-BAIAP2L1 fusion transcripts was not detected in any of the carcinomas, somatic FGFR3 mutations were detected in two (0.9%) LCs. The two mutations were the same, i.e., p.R248H. That was a novel mutation occurring in the same codon as p.R248C, for which an oncogenic potential has previously been shown. Increased FGFR3 expression was shown in the two LCs containing the FGFR3 p.R248H mutation using qPCR. Histologically, both carcinomas were squamous cell carcinomas, therefore the incidence of the FGFR3 mutation among the squamous cell carcinoma cases was calculated as 3.2% (2/63). When we examined other co-occurring genetic abnormalities, one case exhibited a p53 p.R273C mutation, while the other case exhibited PIK3CA and SOX2 amplifications. The above results suggest that an FGFR3 p.R248H mutation is involved in the carcinogenesis of a subset of LCs and may contribute to the elucidation of the characteristics of FGFR3 mutation-positive LCs in the future.

Related: Lung Cancer


Miranda LQ, Fracaroli TS, Fonseca JC, et al.
Analysis of mutations in the PIK3CA and FGFR3 genes in verrucous epidermal nevus.
An Bras Dermatol. 2013 Nov-Dec; 88(6 Suppl 1):36-8 [PubMed] Article available free on PMC after 10/02/2015 Related Publications
Verrucous epidermal nevi are congenital hamartomas composed of keratinocytes and may occur alone or in association with developmental abnormalities. A close relationship between variations in the PIK3CA and FGFR3 genes and the appearance of nevi has been recently reported. Based on that, we performed molecular assays for the identification of E542K, E545G/K and H1047R mutations in the PIK3CA gene and of the R248C mutation in the FGFR3 gene. Interestingly, during the amplification process, we did not observe the PCR product of exon 9 of the PIK3CA gene, a region comprising amino acids 542-545. This strongly suggests the occurrence of a microdeletion of that region and indicates a possible allelic variant, which has not yet being described in the literature.


Hänze J, Henrici M, Hegele A, et al.
Epithelial mesenchymal transition status is associated with anti-cancer responses towards receptor tyrosine-kinase inhibition by dovitinib in human bladder cancer cells.
BMC Cancer. 2013; 13:589 [PubMed] Article available free on PMC after 10/02/2015 Related Publications
BACKGROUND: Dovitinib (TKI-258) is a receptor tyrosine kinase (RTK) inhibitor targeting fibroblast growth factor receptor (FGFR) and further related RTKs. TKI-258 is under investigation as anticancer drug for the treatment of various cancers including bladder cancer with aberrant RTK signaling. Here, we analyzed the responses of ten human bladder cancer cell lines towards TKI-258 treatment in relation to the epithelial mesenchymal transition (EMT) status of the cells.
METHODS: Expression of epithelial marker E-cadherin as well as mesenchymal markers N-cadherin and vimentin was determined by quantitative RT-PCR and Western-blot in RNA and protein extracts from the cultured cell lines. The cell responses were analyzed upon addition of TKI-258 by viability/proliferation (XTT assay) and colony formation assay for measurement of cell contact independent growth.
RESULTS: The investigated bladder cancer cell lines turned out to display quite different EMT patterns as indicated by the abundance of E-cadherin or N-cadherin and vimentin. Protein and mRNA levels of the respective components strongly correlated. Based on E-cadherin and N-cadherin mRNA levels that were expressed approximately mutual exclusively, an EMT-score was calculated for each cell line. A high EMT-score indicated mesenchymal-like cells and a low EMT-score epithelial-like cells. Then, we determined the IC₅₀ values for TKI-258 by dose response curves (0-12 μM TKI-258) in XTT assays for each cell line. Also, we measured the clonogenic survival fraction after adding TKI-258 (1 μM) by colony formation assay. We observed significant correlations between EMT-score and IC₅₀ values (r = 0.637, p = 0.0474) and between EMT-score and clonogenic survival fraction (r = 0.635, p = 0.0483) as analyzed by linear regression analyses.
CONCLUSIONS: In sum, we demonstrated that the EMT status based on E-cadherin and N-cadherin mRNA levels may be useful to predict responses towards TKI-258 treatment in bladder cancer.

Related: Signal Transduction Bladder Cancer Bladder Cancer - Molecular Biology CDH1


Kim Y, Hammerman PS, Kim J, et al.
Integrative and comparative genomic analysis of lung squamous cell carcinomas in East Asian patients.
J Clin Oncol. 2014; 32(2):121-8 [PubMed] Article available free on PMC after 10/01/2015 Related Publications
PURPOSE: Lung squamous cell carcinoma (SCC) is the second most prevalent type of lung cancer. Currently, no targeted therapeutics are approved for treatment of this cancer, largely because of a lack of systematic understanding of the molecular pathogenesis of the disease. To identify therapeutic targets and perform comparative analyses of lung SCC, we probed somatic genome alterations of lung SCC by using samples from Korean patients.
PATIENTS AND METHODS: We performed whole-exome sequencing of DNA from 104 lung SCC samples from Korean patients and matched normal DNA. In addition, copy-number analysis and transcriptome analysis were conducted for a subset of these samples. Clinical association with cancer-specific somatic alterations was investigated.
RESULTS: This cancer cohort is characterized by a high mutational burden with an average of 261 somatic exonic mutations per tumor and a mutational spectrum showing a signature of exposure to cigarette smoke. Seven genes demonstrated statistical enrichment for mutation: TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2, and PIK3CA). Comparative analysis between Korean and North American lung SCC samples demonstrated a similar spectrum of alterations in these two populations in contrast to the differences seen in lung adenocarcinoma. We also uncovered recurrent occurrence of therapeutically actionable FGFR3-TACC3 fusion in lung SCC.
CONCLUSION: These findings provide new steps toward the identification of genomic target candidates for precision medicine in lung SCC, a disease with significant unmet medical needs.

Related: Lung Cancer NFE2L2 gene PTEN RB1 TP53 USA MLL2 gene


Krejci P
The paradox of FGFR3 signaling in skeletal dysplasia: why chondrocytes growth arrest while other cells over proliferate.
Mutat Res Rev Mutat Res. 2014 Jan-Mar; 759:40-8 [PubMed] Related Publications
Somatic mutations in receptor tyrosine kinase FGFR3 cause excessive cell proliferation, leading to cancer or skin overgrowth. Remarkably, the same mutations inhibit chondrocyte proliferation and differentiation in developing bones, resulting in skeletal dysplasias, such as hypochondroplasia, achondroplasia, SADDAN and thanatophoric dysplasia. A similar phenotype is observed in Noonan syndrome, Leopard syndrome, hereditary gingival fibromatosis, neurofibromatosis type 1, Costello syndrome, Legius syndrome and cardiofaciocutaneous syndrome. Collectively termed RASopathies, the latter syndromes are caused by germline mutations in components of the RAS/ERK MAP kinase signaling pathway. This article considers the evidence suggesting that FGFR3 activation in chondrocytes mimics the activation of major oncogenes signaling via the ERK pathway. Subsequent inhibition of chondrocyte proliferation in FGFR3-related skeletal dysplasias and RASopathies is proposed to result from activation of defense mechanisms that originally evolved to safeguard mammalian organisms against cancer.

Related: Bone Cancers Signal Transduction


Dienstmann R, Rodon J, Prat A, et al.
Genomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors.
Ann Oncol. 2014; 25(3):552-63 [PubMed] Related Publications
The fibroblast growth factor receptor (FGFR) cascade plays crucial roles in tumor cell proliferation, angiogenesis, migration and survival. Accumulating evidence suggests that in some tumor types, FGFRs are bona fide oncogenes to which cancer cells are addicted. Because FGFR inhibition can reduce proliferation and induce cell death in a variety of in vitro and in vivo tumor models harboring FGFR aberrations, a growing number of research groups have selected FGFRs as targets for anticancer drug development. Multikinase FGFR/vascular endothelial growth factor receptor (VEGFR) inhibitors have shown promising activity in breast cancer patients with FGFR1 and/or FGF3 amplification. Early clinical trials with selective FGFR inhibitors, which may overcome the toxicity constraints raised by multitarget kinase inhibition, are recruiting patients with known FGFR(1-4) status based on genomic screens. Preliminary signs of antitumor activity have been demonstrated in some tumor types, including squamous cell lung carcinomas. Rational combination of targeted therapies is expected to further increase the efficacy of selective FGFR inhibitors. Herein, we discuss unsolved questions in the clinical development of these agents and suggest guidelines for management of hyperphosphatemia, a class-specific mechanism-based toxicity. In addition, we propose standardized definitions for FGFR1 and FGFR2 gene amplification based on in situ hybridization methods. Extended access to next-generation sequencing platforms will facilitate the identification of diseases in which somatic FGFR(1-4) mutations, amplifications and fusions are potentially driving cancer cell viability, further strengthening the role of FGFR signaling in cancer biology and providing more possibilities for the therapeutic application of FGFR inhibitors.

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Scarpa A, Sikora K, Fassan M, et al.
Molecular typing of lung adenocarcinoma on cytological samples using a multigene next generation sequencing panel.
PLoS One. 2013; 8(11):e80478 [PubMed] Article available free on PMC after 10/01/2015 Related Publications
Identification of driver mutations in lung adenocarcinoma has led to development of targeted agents that are already approved for clinical use or are in clinical trials. Therefore, the number of biomarkers that will be needed to assess is expected to rapidly increase. This calls for the implementation of methods probing the mutational status of multiple genes for inoperable cases, for which limited cytological or bioptic material is available. Cytology specimens from 38 lung adenocarcinomas were subjected to the simultaneous assessment of 504 mutational hotspots of 22 lung cancer-associated genes using 10 nanograms of DNA and Ion Torrent PGM next-generation sequencing. Thirty-six cases were successfully sequenced (95%). In 24/36 cases (67%) at least one mutated gene was observed, including EGFR, KRAS, PIK3CA, BRAF, TP53, PTEN, MET, SMAD4, FGFR3, STK11, MAP2K1. EGFR and KRAS mutations, respectively found in 6/36 (16%) and 10/36 (28%) cases, were mutually exclusive. Nine samples (25%) showed concurrent alterations in different genes. The next-generation sequencing test used is superior to current standard methodologies, as it interrogates multiple genes and requires limited amounts of DNA. Its applicability to routine cytology samples might allow a significant increase in the fraction of lung cancer patients eligible for personalized therapy.

Related: Lung Cancer


Inagaki A, Tajima E, Uranishi M, et al.
Global real-time quantitative reverse transcription-polymerase chain reaction detecting proto-oncogenes associated with 14q32 chromosomal translocation as a valuable marker for predicting survival in multiple myeloma.
Leuk Res. 2013; 37(12):1648-55 [PubMed] Related Publications
CCND1, FGFR3 and c-MAF mRNA expression of tumor samples from 123 multiple myeloma patients were analyzed by global RQ/RT-PCR. CCND1, FGFR3 and c-MAF were positive in 44 (36%), 28 (23%) and 16 (13%) of patients, respectively. In 7 patients, both FGFR3 and c-MAF were positive. The expression of c-MAF was independent unfavorable prognostic factors for overall survival (OS). Autologous stem cell transplantation improved progression-free survival of CCND1-positive patients. Bortezomib, thalidomide or lenalidomide extended OS of FGFR3 and/or c-MAF-positive patients. Thus, CCND1, FGFR3 and c-MAF mRNA expression can predict survival and is useful for planning stratified treatment strategies for myeloma patients.

Related: Chromosome 14 Myeloma Myeloma - Molecular Biology


Calderaro J, Rebouissou S, de Koning L, et al.
PI3K/AKT pathway activation in bladder carcinogenesis.
Int J Cancer. 2014; 134(8):1776-84 [PubMed] Related Publications
The PI3K/AKT pathway is considered to play a major role in bladder carcinogenesis, but its relationships with other molecular alterations observed in bladder cancer remain unknown. We investigated PI3K/AKT pathway activation in a series of human bladder urothelial carcinomas (UC) according to PTEN expression, PTEN deletions and FGFR3, PIK3CA, KRAS, HRAS, NRAS and TP53 gene mutations. The series included 6 normal bladder urothelial samples and 129 UC (Ta n = 25, T1 n = 34, T2-T3-T4 n = 70). Expression of phospho-AKT (pAKT), phospho-S6-Ribosomal Protein (pS6) (one downstream effector of PI3K/AKT pathway) and PTEN was evaluated by reverse phase protein Array. Expression of miR-21, miR-19a and miR-222, known to regulate PTEN expression, was also evaluated. pAKT expression levels were higher in tumors than in normal urothelium (p < 0.01), regardless of stage and showed a weak and positive correlation with pS6 (Spearman coefficient RS = 0.26; p = 0.002). No association was observed between pAKT or pS6 expression and the gene mutations studied. PTEN expression was decreased in PTEN-deleted tumors, and in T1 (p = 0.0089) and T2-T3-T4 (p < 0.001) tumors compared to Ta tumors; it was also negatively correlated with miR-19a (RS = -0.50; p = 0.0088) and miR-222 (RS = -0.48; p = 0.0132), but not miR-21 (RS = -0.27; p = 0.18) expression. pAKT and PTEN expressions were not negatively correlated, and, on the opposite, a positive and moderate correlation was observed in Ta (RS = 0.54; p = 0.0056) and T1 (RS = 0.56; p = 0.0006) tumors. Our study suggests that PI3K/AKT pathway activation occurs in the entire spectrum of bladder UC regardless of stage or known most frequent molecular alterations, and independently of low PTEN expression.

Related: PTEN AKT1 Signal Transduction TP53 Bladder Cancer Bladder Cancer - Molecular Biology KRAS gene miR-21 NRAS


Guo G, Sun X, Chen C, et al.
Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation.
Nat Genet. 2013; 45(12):1459-63 [PubMed] Related Publications
Bladder cancer is one of the most common cancers worldwide, with transitional cell carcinoma (TCC) being the predominant form. Here we report a genomic analysis of TCC by both whole-genome and whole-exome sequencing of 99 individuals with TCC. Beyond confirming recurrent mutations in genes previously identified as being mutated in TCC, we identified additional altered genes and pathways that were implicated in TCC. Notably, we discovered frequent alterations in STAG2 and ESPL1, two genes involved in the sister chromatid cohesion and segregation (SCCS) process. Furthermore, we also detected a recurrent fusion involving FGFR3 and TACC3, another component of SCCS, by transcriptome sequencing of 42 DNA-sequenced tumors. Overall, 32 of the 99 tumors (32%) harbored genetic alterations in the SCCS process. Our analysis provides evidence that genetic alterations affecting the SCCS process may be involved in bladder tumorigenesis and identifies a new therapeutic possibility for bladder cancer.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter Bladder Cancer Bladder Cancer - Molecular Biology


Gyanchandani R, Ortega Alves MV, Myers JN, Kim S
A proangiogenic signature is revealed in FGF-mediated bevacizumab-resistant head and neck squamous cell carcinoma.
Mol Cancer Res. 2013; 11(12):1585-96 [PubMed] Article available free on PMC after 10/01/2015 Related Publications
UNLABELLED: Resistance to antiangiogenic therapies is a critical problem that has limited the utility of antiangiogenic agents in clinical settings. However, the molecular mechanisms underlying this resistance have yet to be fully elucidated. In this study, we established a novel xenograft model of acquired resistance to bevacizumab. To identify molecular changes initiated by the tumor cells, we performed human-specific microarray analysis on bevacizumab-sensitive and -resistant tumors. Efficiency analysis identified 150 genes upregulated and 31 genes downregulated in the resistant tumors. Among angiogenesis-related genes, we found upregulation of fibroblast growth factor-2 (FGF2) and fibroblast growth factor receptor-3 (FGFR3) in the resistant tumors. Inhibition of the FGFR in the resistant tumors led to the restoration of sensitivity to bevacizumab. Furthermore, increased FGF2 production in the resistant cells was found to be mediated by overexpression of upstream genes phospholipase C (PLCg2), frizzled receptor-4 (FZD4), chemokine [C-X3-C motif] (CX3CL1), and chemokine [C-C motif] ligand 5 (CCL5) via extracellular signal-regulated kinase (ERK). In summary, our work has identified an upregulation of a proangiogenic signature in bevacizumab-refractory HNSCC tumors that converges on ERK signaling to upregulate FGF2, which then mediates evasion of anti-VEGF therapy. These findings provide a new strategy on how to enhance the therapeutic efficacy of antiangiogenic therapy.
IMPLICATIONS: Novel xenograft model leads to the discovery of FGF as a promising therapeutic target in overcoming the resistance of antiangiogenic therapy in HNSCC.

Related: Angiogenesis Inhibitors FGF2 Head and Neck Cancers Head and Neck Cancers - Molecular Biology Angiogenesis and Cancer Bevacizumab (Avastin)


Allory Y, Beukers W, Sagrera A, et al.
Telomerase reverse transcriptase promoter mutations in bladder cancer: high frequency across stages, detection in urine, and lack of association with outcome.
Eur Urol. 2014; 65(2):360-6 [PubMed] Related Publications
BACKGROUND: Hotspot mutations in the promoter of the gene coding for telomerase reverse transcriptase (TERT) have been described and proposed to activate gene expression.
OBJECTIVES: To investigate TERT mutation frequency, spectrum, association with expression and clinical outcome, and potential for detection of recurrences in urine in patients with urothelial bladder cancer (UBC).
DESIGN, SETTING, AND PARTICIPANTS: A set of 111 UBCs of different stages was used to assess TERT promoter mutations by Sanger sequencing and TERT messenger RNA (mRNA) expression by reverse transcription-quantitative polymerase chain reaction. The two most frequent mutations were investigated, using a SNaPshot assay, in an independent set of 184 non-muscle-invasive and 173 muscle-invasive UBC (median follow-up: 53 mo and 21 mo, respectively). Voided urine from patients with suspicion of incident UBC (n=174), or under surveillance after diagnosis of non-muscle-invasive UBC (n=194), was tested using a SNaPshot assay.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Association of mutation status with age, sex, tobacco, stage, grade, fibroblast growth factor receptor 3 (FGFR3) mutation, progression-free survival, disease-specific survival, and overall survival.
RESULTS AND LIMITATIONS: In the two series, 78 of 111 (70%) and 283 of 357 (79%) tumors harbored TERT mutations, C228T being the most frequent substitution (83% for both series). TERT mutations were not associated with clinical or pathologic parameters, but were more frequent among FGFR3 mutant tumors (p=0.0002). There was no association between TERT mutations and mRNA expression (p=0.3). Mutations were not associated with clinical outcome. In urine, TERT mutations had 90% specificity in subjects with hematuria but no bladder tumor, and 73% in recurrence-free UBC patients. The sensitivity was 62% in incident and 42% in recurrent UBC. A limitation of the study is its retrospective nature.
CONCLUSIONS: Somatic TERT promoter mutations are an early, highly prevalent genetic event in UBC and are not associated with TERT mRNA levels or disease outcomes. A SNaPshot assay in urine may help to detect UBC recurrences.

Related: Bladder Cancer Bladder Cancer - Molecular Biology TERT


Jantip J, Tanthanuch M, Kanngurn S, et al.
Mutations of fibroblast growth factor receptor 3 gene (FGFR3) in transitional cell carcinoma of urinary bladder in Thai patients [Revision-2a].
J Med Assoc Thai. 2013; 96(8):976-83 [PubMed] Related Publications
OBJECTIVE: Determine the incidence of FGFR3 mutations in Thai patients with bladder transitional cell carcinoma (TCC), and evaluate their correlation with pathological characteristics.
MATERIAL AND METHOD: One hundred twenty two frozen tissue samples from TCC patients were analyzed for mutations in exons 7, 10, and 15 of FGFR3 by polymerase chain reaction and direct DNA sequencing.
RESULTS: FGFR3 mutations were detected in 22 of 122 cases (18%) studied, all of which were found within previously identified hotspots, including S249C (13 cases; 59%) and R248C (4 cases; 18%) in exon 7, and Y375C (5 cases; 23%) in exon 10, but no mutations in exon 15. Sixty-five patients (53%) were categorized as non-muscle-invasive TCC (pTa-pT1). The incidence of mutations is significantly higher in non-muscle-invasive tumors (28%) compared to the muscle-invading group (7%) (p < 0.01). Patients with grade (G) 1 TCC have significantly higher mutation frequency (40%) compared to other grades (4%) (p < 0.01). When T stage and grade were considered together, mutations were most commonly found in Ta-T1/G1 TCC (18/45 cases, 40%). Mean follow-up period was 45.1 months. Two-year and four-year overall survival (OS) was 70% and 56% respectively. Three-year OS in non-muscle-invasive TCC (80%) is significantly higher than that of muscle invading TCC (41%) (p < 0.01). However three-year OS in cases with an FGFR3 mutation (73%) is not significantly different from cases without a mutation (61%). In 16 cases with an FGFR3 mutation and recurrent disease, no mutations were detected in metachronous disease.
CONCLUSION: The overall incidence of FGFR3 mutations in Thai patients with TCC was lower than similar reports from other ethnic groups. In the presented cases, although FGFR3 mutations were frequently detected in low-grade, non-muscle-invasive TCC, identical mutation was not conserved in metachronous disease, thereby precluding the use of this marker in detection of tumor recurrence.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter Thailand Bladder Cancer Bladder Cancer - Molecular Biology


Inazu M, Yamada T, Kubota N, Yamanaka T
Functional expression of choline transporter-like protein 1 (CTL1) in small cell lung carcinoma cells: a target molecule for lung cancer therapy.
Pharmacol Res. 2013; 76:119-31 [PubMed] Related Publications
Choline is essential for the synthesis of the major membrane phospholipid phosphatidylcholine and the neurotransmitter acetylcholine (ACh). Elevated levels of choline and up-regulated choline kinase activity have been detected in cancer cells. Thus, the intracellular accumulation of choline through choline transporters is the rate-limiting step in phospholipid metabolism and a prerequisite for cancer cell proliferation. However, the uptake system for choline and the functional expression of choline transporters in lung cancer cells are poorly understood. We examined the molecular and functional characterization of choline uptake in the small cell lung carcinoma cell line NCI-H69. Choline uptake was saturable and mediated by a single transport system. Interestingly, removal of Na(+) from the uptake buffer strongly enhanced choline uptake. This increase in choline uptake under the Na(+)-free conditions was inhibited by dimethylamiloride (DMA), a Na(+)/H(+) exchanger (NHE) inhibitor. Various organic cations and the choline analog hemicholinium-3 (HC-3) inhibited the choline uptake and cell viability. A correlation analysis of the potencies of organic cations for the inhibition of choline uptake and cell viability showed a strong correlation (R=0.8077). RT-PCR revealed that choline transporter-like protein 1 (CTL1) mRNA and NHE1 are mainly expressed. HC-3 and CTL1 siRNA inhibited choline uptake and cell viability, and increased caspase-3/7 activity. The conversion of choline to ACh was confirmed, and this conversion was enhanced under Na(+)-free conditions, which in turn was sensitive to HC-3. These results indicate that choline uptake through CTL1 is used for ACh synthesis. Both an acetylcholinesterase inhibitor (eserine) and a butyrylcholinesterase inhibitor (ethopropazine) increased cell proliferation, and these effects were inhibited by 4-DAMP, a mAChR3 antagonist. We conclude that NCI-H69 cells express the choline transporter CTL1 which uses a directed H(+) gradient as a driving force, and its transport functions in co-operation with NHE1. This system primarily supplies choline for the synthesis of ACh and secretes ACh to act as an autocrine/paracrine growth factor, and the functional inhibition of CTL1 could promote apoptotic cell death. Identification of this new CTL1-mediated choline transport system provides a potential new target for therapeutic intervention.

Related: Apoptosis Lung Cancer Small Cell Lung Cancer


Lafitte M, Moranvillier I, Garcia S, et al.
FGFR3 has tumor suppressor properties in cells with epithelial phenotype.
Mol Cancer. 2013; 12:83 [PubMed] Article available free on PMC after 10/01/2015 Related Publications
BACKGROUND: Due to frequent mutations in certain cancers, FGFR3 gene is considered as an oncogene. However, in some normal tissues, FGFR3 can limit cell growth and promote cell differentiation. Thus, FGFR3 action appears paradoxical.
RESULTS: FGFR3 expression was forced in pancreatic cell lines. The receptor exerted dual effects: it suppressed tumor growth in pancreatic epithelial-like cells and had oncogenic properties in pancreatic mesenchymal-like cells. Distinct exclusive pathways were activated, STATs in epithelial-like cells and MAP Kinases in mesenchymal-like cells. Both FGFR3 splice variants had similar effects and used the same intracellular signaling. In human pancreatic carcinoma tissues, levels of FGFR3 dropped in tumors.
CONCLUSION: In tumors from epithelial origin, FGFR3 signal can limit tumor growth, explaining why the 4p16.3 locus bearing FGFR3 is frequently lost and why activating mutations of FGFR3 in benign or low grade tumors of epithelial origin are associated with good prognosis. The new hypothesis that FGFR3 can harbor both tumor suppressive and oncogenic properties is crucial in the context of targeted therapies involving specific tyrosine kinase inhibitors (TKIs). TKIs against FGFR3 might result in adverse effects if used in the wrong cell context.

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Ross JS, Wang K, Al-Rohil RN, et al.
Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy.
Mod Pathol. 2014; 27(2):271-80 [PubMed] Related Publications
Although urothelial carcinoma (UC) of the urinary bladder generally portends a favorable prognosis, metastatic tumors often follow an aggressive clinical course. DNA was extracted from 40 μm of formalin-fixed, paraffin-embedded (FFPE) sections from 35 stage IV UCs that had relapsed and progressed after primary surgery and conventional chemotherapy. Next-generation sequencing (NGS) was performed on hybridization-captured, adaptor ligation-based libraries for 3320 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer to at an average sequencing depth of 1164 × and evaluated for all classes of genomic alterations (GAs). Actionable GAs were defined as those impacting the selection of targeted anticancer therapies on the market or in registered clinical trials. A total of 139 GAs were identified, with an average of 4.0 GAs per tumor (range 0-10), of which 78 (56%) were considered actionable, with an average of 2.2 per tumor (range 0-7). Twenty-nine (83%) cases harbored at least one actionable GA including: PIK3CA (9 cases; 26%); CDKN2A/B (8 cases; 23%); CCND1 (5 cases; 14%); FGFR1 (5 cases; 14%); CCND3 (4 cases; 11%); FGFR3 (4 cases; 11%); MCL1 (4 cases; 11%); MDM2 (4 cases; 11%); EGFR (2 cases, 6%); ERBB2 (HER2/neu) (2 cases, 6%); NF1 (2 cases, 6%) and TSC1 (2 cases, 6%). Notable additional alterations included TP53 (19 cases, 54%) and RB1 (6 cases; 17%). Genes involved in chromatin modification were altered by nonsense mutation, splice site mutation or frameshift indel in a mutually exclusive manner in nearly half of all cases including KDM6A (10 cases; 29%) and ARID1A (7 cases; 20%). Comprehensive NGS of 35 UCs of the bladder revealed a diverse spectrum of actionable GAs in 83% of cases, which has the potential to inform treatment decisions for patients with relapsed and metastatic disease.

Related: Transitional Cell Cancer of the Renal Pelvis and Ureter Bladder Cancer Bladder Cancer - Molecular Biology


Kelleher FC, O'Sullivan H, Smyth E, et al.
Fibroblast growth factor receptors, developmental corruption and malignant disease.
Carcinogenesis. 2013; 34(10):2198-205 [PubMed] Related Publications
Fibroblast growth factors (FGF) are a family of ligands that bind to four different types of cell surface receptor entitled, FGFR1, FGFR2, FGFR3 and FGFR4. These receptors differ in their ligand binding affinity and tissue distribution. The prototypical receptor structure is that of an extracellular region comprising three immunoglobulin (Ig)-like domains, a hydrophobic transmembrane segment and a split intracellular tyrosine kinase domain. Alternative gene splicing affecting the extracellular third Ig loop also creates different receptor isoforms entitled FGFRIIIb and FGFRIIIc. Somatic fibroblast growth factor receptor (FGFR) mutations are implicated in different types of cancer and germline FGFR mutations occur in developmental syndromes particularly those in which craniosynostosis is a feature. The mutations found in both conditions are often identical. Many somatic FGFR mutations in cancer are gain-of-function mutations of established preclinical oncogenic potential. Gene amplification can also occur with 19-22% of squamous cell lung cancers for example having amplification of FGFR1. Ontologic comparators can be informative such as aberrant spermatogenesis being implicated in both spermatocytic seminomas and Apert syndrome. The former arises from somatic FGFR3 mutations and Apert syndrome arises from germline FGFR2 mutations. Finally, therapeutics directed at inhibiting the FGF/FGFR interaction are a promising subject for clinical trials.

Related: Cancer Prevention and Risk Reduction


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Cite this page: Cotterill SJ. FGFR3 gene, Cancer Genetics Web: http://www.cancerindex.org/geneweb/FGFR3.htm Accessed: date

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