FGFR3–TACC3: A novel gene fusion in cervical cancer

Carneiro, Benedito A.; Elvin, Julia A.; Kamath, Suneel D.; Ali, Siraj M.; Paintal, Ajit; Restrepo, Alvaro; Berry, Emily; Giles, Francis J.; Johnson, Melissa L.

doi:10.1016/j.gore.2015.06.005

Cited by 57 publications

(46 citation statements)

References 16 publications

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“…Since their initial discovery in the late 1990s, the detection of these fusion proteins has steadily increased at a surprising rate. The focus of this article is a fusion protein consisting of FGFR3 fused to transforming acidic coiled-coil containing protein 3 (TACC3) that has been identified in glioblastoma, lung cancer, bladder cancer, oral cancer, head and neck squamous cell carcinoma, gallbladder cancer, and cervical cancer (1,2). The FGFR3-TACC3 fusion protein is a consequence of a 70 kb tandem duplication at 4p16.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic Gene Fusion FGFR3-TACC3 Is Regulated by Tyrosine Phosphorylation

Nelson

Meyer

Siari

et al. 2016

Molecular Cancer Research

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Fibroblast growth factor receptors (FGFR) are critical for cell proliferation and differentiation. Mutation and/or translocation of FGFRs lead to aberrant signaling that often results in developmental syndromes or cancer growth. As sequencing of human tumors becomes more frequent, so does the detection of FGFR translocations and fusion proteins. The research conducted in this article examines a frequently identified fusion protein between FGFR3 and transforming acidic coiled-coil containing protein 3 (TACC3), frequently identified in glioblastoma, lung cancer, bladder cancer, oral cancer, head and neck squamous cell carcinoma, gallbladder cancer, and cervical cancer. Using titanium dioxide-based phosphopeptide enrichment (TiO 2 )-liquid chromatography (LC)-high mass accuracy tandem mass spectrometry (MS/MS), it was demonstrated that the fused coiled-coil TACC3 domain results in constitutive phosphorylation of key activating FGFR3 tyrosine residues. The presence of the TACC coiled-coil domain leads to increased and altered levels of FGFR3 activation, fusion protein phosphorylation, MAPK pathway activation, nuclear localization, cellular transformation, and IL3-independent proliferation. Introduction of K508R FGFR3 kinase-dead mutation abrogates these effects, except for nuclear localization which is due solely to the TACC3 domain.Implications: These results demonstrate that FGFR3 kinase activity is essential for the oncogenic effects of the FGFR3-TACC3 fusion protein and could serve as a therapeutic target, but that phosphorylated tyrosine residues within the TACC3-derived portion are not critical for activity.

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Section: Introductionmentioning

confidence: 99%

Oncogenic Gene Fusion FGFR3-TACC3 Is Regulated by Tyrosine Phosphorylation

Nelson

Meyer

Siari

et al. 2016

Molecular Cancer Research

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“…FGFR1 amplification and FGFR fusion seem to be of key importance in tumor progression and were illustrated to be new drivers for a range of cancers [16,17]. It was reported that FGFR1 amplification was found in about 10% of breast cancer and located on chromosome 8p12 [18].…”

Section: Discussionmentioning

confidence: 99%

FGFR1 amplification and FGFR gene fusion in resected squamous cell carcinoma of the lung

Wang¹,

Liu²,

Wang³

et al. 2018

biomedicalresearch

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The objective of the present study was to investigate the clinicopathologic characteristics and prognostic role of FGFR1 amplification and FGFR fusion in patients with surgically resected squamous cell carcinoma of the lung (SCCL). Here, fluorescent in situ hybridization (FISH) was performed to detect FGFR1 amplification and reverse transcriptase polymerase chain reaction (RT-PCR) was used to screen 15 known FGFR fusion variants in 108 patients with surgically resected SCCL. All cases were also analyzed for EGFR, KRAS, HER2 and BRAF mutations. Clinical characteristics including age, sex, smoking status, stage, relapse-free survival (RFS) and overall survival (OS) were collected. Of 108 tumors screened, 14 (13.0%) FGFR1 amplification was found. There were 4 (3.7%) patients that harbored FGFR fusion including 2 BAG4-FGFR1 and 2 FGFR3-TACC3 fusion. Compared to the FGFR1 amplification negative group, patients with FGFR1 amplification were more likely to be smokers (100.0%, 14 of 14 patients, p=0.036), significantly associated with larger tumor (>3 cm) (88.2%, 13 of 14 patients, p=0.032). Patients with FGFR1 amplification had worse RFS (p=0.013) and OS (p=0.021) than those without FGFR1 amplification. There was no correlation between FGFR fusion and clinicopathologic characteristics. No significant difference in RFS or OS was found between patients with FGFR fusion and those without FGFR fusion. In conclusion, FGFR1 amplification and FGFR fusion occurred in 13.0% and 3.7% of patients with surgically resected SCCL, separately. FGFR1 amplification was correlated with poor prognosis and identified a distinct subset of SCCL with a higher prevalence among smokers with relative larger tumor (>3 cm). FGFR is a therapeutic target and patients with FGFR1 amplification or FGFR fusion may benefit from FGFR targeted therapy which needs further clinical investigation.

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“…Patient selection by molecular foundation is not yet indicated for metastatic UC. Significant clinical responses were reported in FGFR3-TACC3 fusion-positive cervical cancer patients and glioma patients treated with an FGFR inhibitor[11][14]. However, the FGFR3 mutation is not very frequent among metastatic UC patients, comprising about 6–18% (2/35[38], 2/11[47], and 3/33[48]).…”

Section: Discussionmentioning

confidence: 99%

“…These include the S249C mutation in human BC cells 97–7[12], Y375C mutation in human BC cells MGH-U3[13], and FGFR3-TACC3 fusion in human glioma stem cells GIC-1123[11]. In addition, significant clinical responses to an FGFR inhibitor were reported in FGFR3-TACC3 fusion-positive patients with cervical cancer[14] or glioma[11] in Phase I clinical trials. Thus, detection of not only the activating FGFR3 mutations, especially in exons 7, 10 and 15, but also the FGFR3-TACC3 fusion in BC patients could be clinically important to identify responders to FGFR kinase inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Development of RNA-FISH Assay for Detection of Oncogenic FGFR3-TACC3 Fusion Genes in FFPE Samples

et al. 2016

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Introduction and ObjectivesOncogenic FGFR3-TACC3 fusions and FGFR3 mutations are target candidates for small molecule inhibitors in bladder cancer (BC). Because FGFR3 and TACC3 genes are located very closely on chromosome 4p16.3, detection of the fusion by DNA-FISH (fluorescent in situ hybridization) is not a feasible option. In this study, we developed a novel RNA-FISH assay using branched DNA probe to detect FGFR3-TACC3 fusions in formaldehyde-fixed paraffin-embedded (FFPE) human BC samples.Materials and MethodsThe RNA-FISH assay was developed and validated using a mouse xenograft model with human BC cell lines. Next, we assessed the consistency of the RNA-FISH assay using 104 human BC samples. In this study, primary BC tissues were stored as frozen and FFPE tissues. FGFR3-TACC3 fusions were independently detected in FFPE sections by the RNA-FISH assay and in frozen tissues by RT-PCR. We also analyzed the presence of FGFR3 mutations by targeted sequencing of genomic DNA extracted from deparaffinized FFPE sections.ResultsFGFR3-TACC3 fusion transcripts were identified by RNA-FISH and RT-PCR in mouse xenograft FFPE tissues using the human BC cell lines RT112 and RT4. These cell lines have been reported to be fusion-positive. Signals for FGFR3-TACC3 fusions by RNA-FISH were positive in 2/60 (3%) of non-muscle-invasive BC (NMIBC) and 2/44 (5%) muscle-invasive BC (MIBC) patients. The results of RT-PCR of all 104 patients were identical to those of RNA-FISH. FGFR3 mutations were detected in 27/60 (45%) NMIBC and 8/44 (18%) MIBC patients. Except for one NMIBC patient, FGFR3 mutation and FGFR3-TACC3 fusion were mutually exclusive.ConclusionsWe developed an RNA-FISH assay for detection of the FGFR3-TACC3 fusion in FFPE samples of human BC tissues. Screening for not only FGFR3 mutations, but also for FGFR3-TACC3 fusion transcripts has the potential to identify additional patients that can be treated with FGFR inhibitors.

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FGFR3–TACC3: A novel gene fusion in cervical cancer

Cited by 57 publications

References 16 publications

Oncogenic Gene Fusion FGFR3-TACC3 Is Regulated by Tyrosine Phosphorylation

Oncogenic Gene Fusion FGFR3-TACC3 Is Regulated by Tyrosine Phosphorylation

FGFR1 amplification and FGFR gene fusion in resected squamous cell carcinoma of the lung

Development of RNA-FISH Assay for Detection of Oncogenic FGFR3-TACC3 Fusion Genes in FFPE Samples

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