FGFR3

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:NCBIAccessed: 28 February, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 28 February 2015 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 28 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

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

Latest Publications: FGFR3 (cancer-related)

Geller MD, Pei Y, Spurgeon SE, et al.
Chronic lymphocytic leukemia with a FGFR3 translocation: case report and literature review of an uncommon cytogenetic event.
Cancer Genet. 2014 Jul-Aug; 207(7-8):340-3 [PubMed] Related Publications
The t(4;14) (p16; q32) with fusion of the IGH (immunoglobulin heavy chain) and FGFR3 (fibroblast growth factor receptor 3) genes are rarely present in patients with chronic lymphocytic leukemia (CLL), with only two previously reported cases. We herein describe a unique case of CLL with the occurrence of a t(4;14) (p16;q32), trisomy 12, and deletion of 11q13-q23 in the same clonal cells. In contrast to myeloma, in which FGFR3 translocations are a common early cytogenetic hit, FGFR3 rearrangement in CLL appears to occur later in the disease course.

Chinen Y, Kuroda J, Shimura Y, et al.
Phosphoinositide protein kinase PDPK1 is a crucial cell signaling mediator in multiple myeloma.
Cancer Res. 2014; 74(24):7418-29 [PubMed] Related Publications
Multiple myeloma is a cytogenetically/molecularly heterogeneous hematologic malignancy that remains mostly incurable, and the identification of a universal and relevant therapeutic target molecule is essential for the further development of therapeutic strategy. Herein, we identified that 3-phosphoinositide-dependent protein kinase 1 (PDPK1), a serine threonine kinase, is expressed and active in all eleven multiple myeloma-derived cell lines examined regardless of the type of cytogenetic abnormality, the mutation state of RAS and FGFR3 genes, or the activation state of ERK and AKT. Our results revealed that PDPK1 is a pivotal regulator of molecules that are essential for myelomagenesis, such as RSK2, AKT, c-MYC, IRF4, or cyclin Ds, and that PDPK1 inhibition caused the growth inhibition and the induction of apoptosis with the activation of BIM and BAD, and augmented the in vitro cytotoxic effects of antimyeloma agents in myeloma cells. In the clinical setting, PDPK1 was active in myeloma cells of approximately 90% of symptomatic patients at diagnosis, and the smaller population of patients with multiple myeloma exhibiting myeloma cells without active PDPK1 showed a significantly less frequent proportion of the disease stage III by the International Staging System and a significantly more favorable prognosis, including the longer overall survival period and the longer progression-free survival period by bortezomib treatment, than patients with active PDPK1, suggesting that PDPK1 activation accelerates the disease progression and the resistance to treatment in multiple myeloma. Our study demonstrates that PDPK1 is a potent and a universally targetable signaling mediator in multiple myeloma regardless of the types of cytogenetic/molecular profiles.

Rampias T, Vgenopoulou P, Avgeris M, et al.
A new tumor suppressor role for the Notch pathway in bladder cancer.
Nat Med. 2014; 20(10):1199-205 [PubMed] Related Publications
The Notch signaling pathway controls cell fates through interactions between neighboring cells by positively or negatively affecting the processes of proliferation, differentiation and apoptosis in a context-dependent manner. This pathway has been implicated in human cancer as both an oncogene and a tumor suppressor. Here we report new inactivating mutations in Notch pathway components in over 40% of human bladder cancers examined. Bladder cancer is the fourth most commonly diagnosed malignancy in the male population of the United States. Thus far, driver mutations in fibroblast growth factor receptor 3 (FGFR3) and, less commonly, in RAS proteins have been identified. We show that Notch activation in bladder cancer cells suppresses proliferation both in vitro and in vivo by directly upregulating dual-specificity phosphatases (DUSPs), thus reducing the phosphorylation of ERK1 and ERK2 (ERK1/2). In mouse models, genetic inactivation of Notch signaling leads to Erk1/2 phosphorylation, resulting in tumorigenesis in the urinary tract. Collectively our findings show that loss of Notch activity is a driving event in urothelial cancer.

Trietsch MD, Spaans VM, ter Haar NT, et al.
CDKN2A(p16) and HRAS are frequently mutated in vulvar squamous cell carcinoma.
Gynecol Oncol. 2014; 135(1):149-55 [PubMed] Related Publications
BACKGROUND: Two etiologic pathways of vulvar cancer are known, a human papillomavirus (HPV)- and a TP53-associated route, respectively, but other genetic changes may also play a role. Studies on somatic mutations in vulvar cancer other than TP53 are limited in number and size. In this study, we investigated the prevalence of genetic mutations in 107 vulvar squamous cell carcinomas (VSCCs).
METHODS: A total of 107 paraffin-embedded tissue samples of primarily surgically treated VSCCs were tested for HPV infection and screened for mutations in 14 genes (BRAF, CDKN2A(p16), CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, PTEN, and TP53) using Sanger sequencing and mass spectrometry.
RESULTS: Mutations were detected in 7 genes. Of 107 VSCCs, 66 tumors (62%) contained at least one mutation (TP53=58, CDKN2A(p16)=14, HRAS=10, PIK3CA=7, PPP2R1A=3, KRAS=1, PTEN=1). Mutations occurred most frequently in HPV-negative samples. Five-year survival was significantly worse for patients with a mutation (47% vs 59%, P=.035), with a large effect from patients carrying HRAS-mutations.
CONCLUSION: Somatic mutations were detected in 62% of VSCCs. As expected, HPV infection and TP53-mutations play a key role in the development of VSCC, but CDKN2A(p16), HRAS, and PIK3CA-mutations were also frequently seen in HPV-negative patients. Patients with somatic mutations, especially HRAS-mutations, have a significantly worse prognosis than patients lacking these changes, which could be of importance for the development of targeted therapy.

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.

Choi W, Czerniak B, Ochoa A, et al.
Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer.
Nat Rev Urol. 2014; 11(7):400-10 [PubMed] Related Publications
Whole-genome analyses have revealed that muscle-invasive bladder cancers (MIBCs) are heterogeneous and can be grouped into basal and luminal subtypes that are highly reminiscent of those found in breast cancer. Basal MIBCs are enriched with squamous and sarcomatoid features and are associated with advanced stage and metastatic disease at presentation. Like basal breast cancers, basal bladder tumours contain a claudin-low subtype that is enriched with biomarkers characteristic of epithelial-to-mesenchymal transition. The stem cell transcription factor ΔNp63α controls basal MIBC gene expression, just as it does in basal breast cancers. Luminal MIBCs are enriched with activating FGFR3 and ERBB3 mutations and ERBB2 amplifications, and their gene expression profiles are controlled by peroxisome proliferator activator receptor γ (PPARγ) and possibly also by oestrogen receptor activation. Luminal bladder cancers can be further subdivided into two subtypes, p53-like and luminal, which can be distinguished from one another by different levels of biomarkers that are characteristic of stromal infiltration, cell cycle progression, and proliferation. Importantly, basal bladder cancers are intrinsically aggressive, but are highly sensitive to cisplatin-based combination chemotherapy. Although the luminal subtypes are not as intrinsically aggressive as basal cancers, p53-like tumours are resistant to chemotherapy and might, therefore, represent a problem for treated patients.

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.

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.

Türkmen S, Binder A, Gerlach A, et al.
High prevalence of immunoglobulin light chain gene aberrations as revealed by FISH in multiple myeloma and MGUS.
Genes Chromosomes Cancer. 2014; 53(8):650-6 [PubMed] Related Publications
Multiple myeloma (MM) is a malignant B-cell neoplasm characterized by an uncontrolled proliferation of aberrant plasma cells in the bone marrow. Chromosome aberrations in MM are complex and represent a hallmark of the disease, involving many chromosomes that are altered both numerically and structurally. Nearly half of the cases are nonhyperdiploid and show IGH translocations with the following partner genes: CCND1, FGFR3 and MMSET, MAF, MAFB, and CCND3. The remaining 50% are grouped into a hyperdiploid group that is characterized by multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 21. In this study, we analyzed the immunoglobulin light chain kappa (IGK, 2p12) and lambda (IGL, 22q11) loci in 150 cases, mostly with MM but in a few cases monoclonal gammopathy of undetermined significance (MGUS), without IGH translocations. We identified aberrations in 27% (= 40 patients) including rearrangements (12%), gains (12%), and deletions (4.6%). In 6 of 18 patients with IGK or/and IGL rearrangements, we detected a MYC rearrangement which suggests that MYC is the translocation partner in the majority of these cases.

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.

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.

Tian E, Sawyer JR, Heuck CJ, et al.
In multiple myeloma, 14q32 translocations are nonrandom chromosomal fusions driving high expression levels of the respective partner genes.
Genes Chromosomes Cancer. 2014; 53(7):549-57 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
In studies of patients with multiple myeloma (MM), gene expression profiling (GEP) of myeloma cells demonstrates substantially higher expression of MMSET, FGFR3, CCND3, CCND1, MAF, and MAFB--the partner genes of 14q32 translocations--than GEP of plasma cells from healthy individuals. Interphase fluorescent in situ hybridization (FISH) was used to discriminate between chromosomal translocations involving different regions of the immunoglobulin heavy chain (IGH) genes at 14q32. With special probes designed for the constant region (IGHC) and the variable region (IGHV), IGH translocations were shown to be definite, nonrandom chromosomal fusions of IGHC with the loci of FGFR3, CCND1, CCND3, MAF, and MAFB genes; and IGHV with the locus of MMSET gene. When correlated with GEP results, the IGH translocations were found to drive expression levels of the partner genes to significantly higher levels (spikes) than copy-number variations. Hence, 42% of IGH translocations were identified among newly diagnosed MM patients (448/1,060). As GEP has become essential for assessing cancer risk, this novel approach is highly consistent with the cytogenetic features of the chromosomal translocations to effectively stratify molecular subgroups of MM on the basis of gene expression profiles of the IGH translocation partner genes in myeloma cells. © 2014 Wiley Periodicals, Inc.

Liu X, Zhang W, Geng D, et al.
Clinical significance of fibroblast growth factor receptor-3 mutations in bladder cancer: a systematic review and meta-analysis.
Genet Mol Res. 2014; 13(1):1109-20 [PubMed] Related Publications
Mutations in the fibroblast growth factor receptor-3 (FGFR3) gene are frequently found in bladder cancer, but their prognostic value remains controversial. To globally summarize the association between FGFR3 mutations and the grade and stage of bladder cancer, and to analyze the predictive role of FGFR3 mutations with respect to survival, eligible studies were identified and assessed for quality through multiple search strategies. Risk ratio (RR) data were collected from studies comparing the number of FGFR3 mutants among low-grade and early-stage bladder cancer patients to the number among high-grade and late-stage patients. Hazard ratio (HR) data were collected from studies comparing survival in patients with mutant FGFR3 genes to those with wild-type genes. Studies were pooled, and the RRs of grade and stage and the HRs of survival were calculated. Thirty studies were included in the present meta-analysis. FGFR3 mutations were found to be closely associated with low-grade and early-stage bladder cancer, showing pooled RRs = 2.948 [95% confidence interval (CI) = 2.357-3.688] and 2.845 (95%CI = 2.145- 3.773), respectively. Notably, patients with FGFR3 mutations tended to show better disease-, progress-, and recurrence-free survival (HR = 0.561, 95%CI = 0.405-0.779), and better disease-specific survival (HR = 0.363, 95%CI = 0.266-0.496). This study demonstrated that FGFR3 mutations are closely related to low grade, early stage, and better survival among bladder cancer patients.

Meric-Bernstam F, Frampton GM, Ferrer-Lozano J, et al.
Concordance of genomic alterations between primary and recurrent breast cancer.
Mol Cancer Ther. 2014; 13(5):1382-9 [PubMed] Related Publications
There is growing interest in delivering genomically informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 3,320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy-number alterations (CNA), and select rearrangements were assessed in 74 tumors from 43 patients (36 primary and 38 recurrence/metastases). Alterations potentially targetable with established or investigational therapeutics were considered "actionable." Alterations were detected in 55 genes (mean 3.95 alterations/sample, range 1-12), including mutations in PIK3CA, TP53, ARID1A, PTEN, AKT1, NF1, FBXW7, and FGFR3 and amplifications in MCL1, CCND1, FGFR1, MYC, IGF1R, MDM2, MDM4, AKT3, CDK4, and AKT2. In 33 matched primary and recurrent tumors, 97 of 112 (86.6%) somatic mutations were concordant. Of identified CNAs, 136 of 159 (85.5%) were concordant: 37 (23.3%) were concordant, but below the reporting threshold in one of the matched samples, and 23 (14.5%) discordant. There was an increased frequency of CDK4/MDM2 amplifications in recurrences, as well as gains and losses of other actionable alterations. Forty of 43 (93%) patients had actionable alterations that could inform targeted treatment options. In conclusion, deep genomic profiling of cancer-related genes reveals potentially actionable alterations in most patients with breast cancer. Overall there was high concordance between primary and recurrent tumors. Analysis of recurrent tumors before treatment may provide additional insights, as both gains and losses of targets are observed.

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.

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 01/07/2015 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.

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 01/07/2015 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.


Comprehensive molecular characterization of urothelial bladder carcinoma.
Nature. 2014; 507(7492):315-22 [PubMed] Article available free on PMC after 01/07/2015 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.

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 01/07/2015 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.

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 01/07/2015 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.

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.

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.

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.

Dancik GM, Owens CR, Iczkowski KA, Theodorescu D
A cell of origin gene signature indicates human bladder cancer has distinct cellular progenitors.
Stem Cells. 2014; 32(4):974-82 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
There are two distinct forms of urothelial (bladder) cancer: muscle-invasive (MI) and nonmuscle invasive (NMI) disease. Since it is currently believed that bladder cancer arises by transformation of urothelial cells of the basal layer, bladder cancer stem cells (CSCs) have been isolated based on expression markers found in such cells. However, these CSCs have only been identified in MI tumors raising the intriguing hypothesis that NMI tumor progenitors do not arise from the basal compartment. To test this hypothesis, we carried out genome-wide expression profiling of laser capture microdissected basal and umbrella cells, the two most histologically distinct cell types in normal urothelium and developed a cell of origin (COO) gene signature that distinguishes these. The COO signature was a better predictor of stage and survival than other bladder, generic, or breast CSC signatures and bladder cell differentiation markers in multiple patient cohorts. To assess whether NMI and MI tumors arise from a distinct progenitor cell (DPC) or common progenitor cell, we developed a novel statistical framework that predicts COO score as a function of known genetic alterations (TP53, HRAS, KDM6A, and FGFR3) that drive either MI or NMI bladder cancer and compared this to the observed COO score of the tumor. Analysis of 874 patients in five cohorts established the DPC model as the best fit to the available data. This observation supports distinct progenitor cells in NMI and MI tumors and provides a paradigm shift in our understanding of bladder cancer biology that has significant diagnostic and therapeutic implications.

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 01/04/2015 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 01/04/2015 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.

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 01/04/2015 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.

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.

Fassan M, Simbolo M, Bria E, et al.
High-throughput mutation profiling identifies novel molecular dysregulation in high-grade intraepithelial neoplasia and early gastric cancers.
Gastric Cancer. 2014; 17(3):442-9 [PubMed] Related Publications
BACKGROUND: There is still no widely accepted molecular marker available to distinguish between gastric high-grade intraepithelial neoplasia (HG-IEN) and invasive early gastric cancer (EGC).
METHODS: HG-IEN and EGC lesions coexisting in the same patient were manually microdissected from a series of 15 gastrectomies for EGC; 40 ng DNA was used for multiplex PCR amplification using the Ion AmpliSeq Cancer Panel, which explores the mutational status of hotspot regions in 50 cancer-associated genes.
RESULTS: Of the 15 EGCs, 12 presented at least one somatic mutation among the 50 investigated genes, and 6 of these showed multiple driver gene somatic mutations. TP53 mutations were observed in 9 cases; APC mutations were identified in 3 cases; and ATM and STK11 were mutated in 2 cases. Seven HG-IEN lesions shared an identical mutational profile with the EGC from the same patient; 13 mutations observed in APC, ATM, FGFR3, PIK3CA, RB1, STK11, and TP53 genes were shared by both HG-IEN and ECG lesions. CDKN2A, IDH2, MET, and RET mutations were observed only in EGC. TP53 deregulation was further investigated in an independent series of 75 biopsies corresponding to all the phenotypic lesions occurring in the EGC carcinogenetic cascade. p53 nuclear immunoreaction progressively increased along with the dedifferentiation of the lesions (P < 0.001). Overall, 18 of 20 p53-positive lesions showed a TP53 mutated gene.
DISCUSSION: Our results support the molecular similarity between HG-IEN and EGC and suggest a relevant role for TP53 in the progression to the invasive phenotype and the use of immunohistochemistry as a surrogate to detect TP53 gene mutations.

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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Cite this page: Cotterill SJ. FGFR3 gene, Cancer Genetics Web: http://www.cancer-genetics.org/FGFR3.htm Accessed:

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