FGFR4 Gly388Arg polymorphism may affect the clinical stage of patients with lung cancer by modulating the transcriptional profile of normal lung

Falvella, Felicia Stefania; Frullanti, Elisa; Galvan, Antonella; Spinola, Monica; Noci, Sara; Cecco, Loris De; Nosotti, Mario; Santambrogio, Luigi; Incarbone, Matteo; Alloisio, Marco; Calabrò, Elisa; Pastorino, Ugo; Skaug, Vidar; Haugen, Aage; Taioli, Emanuela; Dragani, Tommaso A.

doi:10.1002/ijc.24302

Cited by 36 publications

(40 citation statements)

References 18 publications

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“…A mixture of 1.5 ug of the biotinylated cRNA sample and Hyb E1 hybridization buffer containing 37.5% (w/w) formamide was hybridized on a mouse WG6 chip on an Illumina platform (Illumina, San Diego, CA, USA) as described. 23 Three biological and two technical replicates were performed. BRB array tool was used to identify differentially expressed genes with a detection P value o0.001.…”

Section: Microarray Analysismentioning

confidence: 99%

Altered expression of neuropeptides in FoxG1-null heterozygous mutant mice

et al. 2015

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Foxg1 gene encodes for a transcription factor essential for telencephalon development in the embryonic mammalian forebrain. Its complete absence is embryonic lethal while Foxg1 heterozygous mice are viable but display microcephaly, altered hippocampal neurogenesis and behavioral and cognitive deficiencies. In order to evaluate the effects of Foxg1 alteration in adult brain, we performed expression profiling in total brains from Foxg1+/ − heterozygous mutants and wild-type littermates. We identified statistically significant differences in expression levels for 466 transcripts (Po0.001), 29 of which showed a fold change ≥ 1.5. Among the differentially expressed genes was found a group of genes expressed in the basal ganglia and involved in the control of movements. A relevant (three to sevenfold changes) and statistically significant increase of expression, confirmed by qRT-PCR, was found in two highly correlated genes with expression restricted to the hypothalamus: Oxytocin (Oxt) and Arginine vasopressin (Avp). These neuropeptides have an important role in maternal and social behavior, and their alteration is associated with impaired social interaction and autistic behavior. In addition, Neuronatin (Nnat) levels appear significantly higher both in Foxg1+/ − whole brain and in hippocampal neurons after silencing Foxg1, strongly suggesting that it is directly or indirectly repressed by Foxg1. During fetal and neonatal brain development, Nnat may regulate neuronal excitability, receptor trafficking and calcium-dependent signaling and, in the adult brain, it is predominantly expressed in parvalbumin-positive GABAergic interneurons. Overall, these results implicate the overexpression of a group of neuropeptides in the basal ganglia, hypothalamus, cortex and hippocampus in the pathogenesis FOXG1 behavioral impairments.

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Section: Microarray Analysismentioning

confidence: 99%

Altered expression of neuropeptides in FoxG1-null heterozygous mutant mice

et al. 2015

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“…A polymorphism in FGFR4 (9) characterized by conversion of guanine to adenine at position 1,217 in exon 9 results in the substitution of arginine for glycine at codon 388 in the transmembrane domain; 40% to 50% of Caucasians carry at least one copy of this allele. The FGFR4-R388 allele is associated with poor outcomes in cohorts of sarcoma (10), prostate (11), lung (12,13), and head and neck carcinomas (14) and in those with advanced and treatment-resistant breast cancer (15). The corresponding mouse SNP accelerates breast cancer progression (16).…”

Section: Introductionmentioning

confidence: 99%

The FGFR4-G388R Single-Nucleotide Polymorphism Alters Pancreatic Neuroendocrine Tumor Progression and Response to mTOR Inhibition Therapy

et al. 2012

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Pancreatic neuroendocrine tumors (pNET), also known as islet cell tumors, exhibit a wide range of biologic behaviors ranging from long dormancy to rapid progression. Currently, there are few molecular biomarkers that can be used to predict recurrence/metastasis or response to therapy. This study examined the predictive and prognostic value of a single nucleotide polymorphism substituting an arginine (R) for glycine (G) in codon 388 of the FGFR4 transmembrane domain. We established the FGFR4 genotype of 71 patients with pNETs and correlated genotype with biologic behavior. We created an in vivo model of pNET with BON1 cells and transfected them with either FGFR4-G388 or FGFR4-R388 to determine the mechanism of action and to examine response to the mTOR inhibitor everolimus. We then validated the predictive results of experimental studies in a group of patients treated with everolimus. FGFR4-R388 is associated with more aggressive clinical behavior in patients with pNETs with a statistically significant higher risk of advanced tumor stage and liver metastasis. Using an orthotopic mouse xenograft model, we show that FGFR4-R388 promotes tumor progression by increasing intraperitoneal spread and metastatic growth within the liver. Unlike FGFR4-G388, FGFR4-R388 BON1 tumors exhibited diminished responsiveness to everolimus. Concordantly, there was a statistically significant reduction in response to everolimus in patients with FGFR4-R388. Our findings highlight the importance of the FGFR4 allele in pNET progression and identify a predictive marker of potential therapeutic importance in this disease. Cancer Res; 72(22); 5683-91. Ó2012 AACR.

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“…A single-nucleotide polymorphism (SNP) in the fibroblast growth factor receptor isoform 4 gene (FGFR4), causing a conversion of guanine to adenine at position 1.217 in exon 9 (FGFR4-G388R), has been reported to associate with a worse prognosis in several human cancers (Morimoto et al 2003, Wang et al 2004, Thussbas et al 2006, da Costa Andrade et al 2007, Sasaki et al 2008, Falvella et al 2009). Serra et al (2012) showed that, in pNET patients, the FGFR4-G388R allele (assessed at germline level) associates with a tumour diameter O2 cm, local invasiveness, lymphovascular invasion, lymph node and liver metastases.…”

Section: Methodsmentioning

confidence: 99%

Predictive factors of response to mTOR inhibitors in neuroendocrine tumours

Zatelli¹,

Fanciulli²,

Malandrino³

et al. 2015

Endocrine-Related Cancer

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Medical treatment of neuroendocrine tumours (NETs) has drawn a lot of attention due to the recent demonstration of efficacy of several drugs on progression-free survival, including somatostatin analogs, small tyrosine kinase inhibitors and mTOR inhibitors (or rapalogs). The latter are approved as therapeutic agents in advanced pancreatic NETs and have been demonstrated to be effective in different types of NETs, with variable efficacy due to the development of resistance to treatment. Early detection of patients that may benefit from rapalogs treatment is of paramount importance in order to select the better treatment and avoid ineffective and expensive treatments. Predictive markers for therapeutic response are under intensive investigation, aiming at a tailored patient management and more appropriate resource utilization. This review summarizes the available data on the tissue, circulating and imaging markers that are potentially predictive of rapalog efficacy in NETs.

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FGFR4 Gly388Arg polymorphism may affect the clinical stage of patients with lung cancer by modulating the transcriptional profile of normal lung

Cited by 36 publications

References 18 publications

Altered expression of neuropeptides in FoxG1-null heterozygous mutant mice

Altered expression of neuropeptides in FoxG1-null heterozygous mutant mice

The FGFR4-G388R Single-Nucleotide Polymorphism Alters Pancreatic Neuroendocrine Tumor Progression and Response to mTOR Inhibition Therapy

Predictive factors of response to mTOR inhibitors in neuroendocrine tumours

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