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

Kurobe, Masayuki; Kojima, Takahiro; Nishimura, Kenichi; Kandori, Shuya; Kawahara, Takashi; Yoshino, Takayuki; Ueno, S.; Iizumi, Yuichi; Mitsuzuka, Koji; Arai, Yoichi; Habuchi, Tomonori; Kobayashi, Takashi; Matsui, Yoshiyuki; Ogawa, Osamu; Sugimoto, Mikio; Kakehi, Yoshiyuki; Nagumo, Yoshiyuki; Tsutsumi, Masahiro; Oikawa, Takehiro; Kikuchi, Koji; Nishiyama, Hiroyuki

doi:10.1371/journal.pone.0165109

Cited by 21 publications

(12 citation statements)

References 43 publications

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“…Confirmation of the FGFR3‐TACC3 fusion requires RT‐PCR followed by sequencing of the in‐frame fusion breakpoint. Direct detection of FGFR3‐TACC3 by RNA‐FISH could be useful . Indeed it could become an important theranostic marker if the benefit of FGFR3 inhibitors in these tumors is confirmed by ongoing clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Diffuse gliomas with FGFR3‐TACC3 fusion have characteristic histopathological and molecular features

et al. 2017

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Adult glioblastomas, IDH-wildtype represent a heterogeneous group of diseases. They are resistant to conventional treatment by concomitant radiochemotherapy and carry a dismal prognosis. The discovery of oncogenic gene fusions in these tumors has led to prospective targeted treatments, but identification of these rare alterations in practice is challenging. Here, we report a series of 30 adult diffuse gliomas with an in frame FGFR3-TACC3 oncogenic fusion (n = 27 WHO grade IV and n = 3 WHO grade II) as well as their histological and molecular features. We observed recurrent morphological features (monomorphous ovoid nuclei, nuclear palisading and thin parallel cytoplasmic processes, endocrinoid network of thin capillaries) associated with frequent microcalcifications and desmoplasia. We report a constant immunoreactivity for FGFR3, which is a valuable method for screening for the FGFR3-TACC3 fusion with 100% sensitivity and 92% specificity. We confirmed the associated molecular features (typical genetic alterations of glioblastoma, except the absence of EGFR amplification, and an increased frequency of CDK4 and MDM2 amplifications). FGFR3 immunopositivity is a valuable tool to identify gliomas that are likely to harbor the FGFR3-TACC3 fusion for inclusion in targeted therapeutic trials.

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Section: Discussionmentioning

confidence: 99%

Diffuse gliomas with FGFR3‐TACC3 fusion have characteristic histopathological and molecular features

et al. 2017

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“…This prospective multicenter cohort study included 144 patients with clinical diagnosis of urothelial carcinoma from seven institutions [25]. The research protocol was approved by the Ethics Committee of Tsukuba University Hospital (Approval number: H25-116).…”

Section: Methodsmentioning

confidence: 99%

TP53 codon 72 polymorphism is associated with FGFR3 and RAS mutation in non-muscle-invasive bladder cancer

et al. 2019

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Objective TP53 , a well-known tumor-suppressor gene in bladder carcinogenesis, has a functional single-nucleotide polymorphism on codon 72. The aim of this study was to elucidate the association between TP53 codon 72 polymorphism and somatic mutations in bladder cancer. Material and methods Germline TP53 codon 72 polymorphism and somatic mutations of 50 cancer-associated genes were analyzed in 103 bladder cancer patients (59 non-muscle-invasive and 44 muscle-invasive), using Taqman genotyping assay and target sequencing, respectively. The expression of FGF-FGFR signaling pathway genes was analyzed by RNA sequencing of frozen tissue. Results The allele frequency of TP53 codon 72 in our cohort was 37, 42, and 21% for Arg/Arg, Arg/Pro, and Pro/Pro, respectively. Interestingly, the prevalence of FGFR3 mutation was higher in patients with the Arg allele, whereas that of the RAS mutation was higher in patients without the Arg allele. The same association was seen in non-muscle-invasive bladder cancer (NMIBC) patients and no differences were observed in muscle-invasive bladder cancer patients. In NMIBC, FGFR1 expression was higher in patients without the Arg allele and FGFR3 expression was higher in patients with the Arg allele. Conclusion The germline TP53 codon 72 polymorphism was associated with mutations of FGFR3 or RAS and expression of FGFR1 and FGFR3 in NMIBC. These findings provide new insight into the molecular mechanisms underlying the influence of the genetic background on carcinogenesis in bladder cancer.

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“…FISH analysis, using break-apart probes, has been frequently used to detect FGFR fusions in clinical samples [36,44]. Recently, a novel RNA-FISH assay allowed the detection of FGFR3-TACC3 fusions in bladder cancer [49].…”

Section: Approaches To Detect Fgfr Fusions In Clinical Diagnosticsmentioning

confidence: 99%

FGFR Fusions in Cancer: From Diagnostic Approaches to Therapeutic Intervention

Luca

Abate

Rachiglio

et al. 2020

IJMS

101

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Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors involved in many biological processes. Deregulated FGFR signaling plays an important role in tumor development and progression in different cancer types. FGFR genomic alterations, including FGFR gene fusions that originate by chromosomal rearrangements, represent a promising therapeutic target. Next-generation-sequencing (NGS) approaches have significantly improved the discovery of FGFR gene fusions and their detection in clinical samples. A variety of FGFR inhibitors have been developed, and several studies are trying to evaluate the efficacy of these agents in molecularly selected patients carrying FGFR genomic alterations. In this review, we describe the most frequent FGFR aberrations in human cancer. We also discuss the different approaches employed for the detection of FGFR fusions and the potential role of these genomic alterations as prognostic/predictive biomarkers.

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

Cited by 21 publications

References 43 publications

Diffuse gliomas with FGFR3‐TACC3 fusion have characteristic histopathological and molecular features

Diffuse gliomas with FGFR3‐TACC3 fusion have characteristic histopathological and molecular features

TP53 codon 72 polymorphism is associated with FGFR3 and RAS mutation in non-muscle-invasive bladder cancer

FGFR Fusions in Cancer: From Diagnostic Approaches to Therapeutic Intervention

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