scholarly journals Fibroblast growth factor (FGF), FGF receptor (FGFR), and cyclin D1 (CCND1) DNA methylation in head and neck squamous cell carcinomas is associated with transcriptional activity, gene amplification, human papillomavirus (HPV) status, and sensitivity to tyrosine kinase inhibitors

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Yilin Bao ◽  
Jennis Gabrielpillai ◽  
Jörn Dietrich ◽  
Romina Zarbl ◽  
Sebastian Strieth ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Gene Amplification ◽  
Targeted Therapies ◽  
Tumor Tissue ◽  
Kinase Inhibitors ◽  
Fibroblast Growth ◽  
Adjacent Tissue ◽  
Cpg Sites

Abstract Background Dysregulation of fibroblast growth factor receptor (FGFR) signaling pathway has been observed in head and neck squamous cell carcinoma (HNSCC) and is a promising therapeutic target for selective tyrosine kinase inhibitors (TKIs). Potential predictive biomarkers for response to FGFR-targeted therapies are urgently needed. Understanding the epigenetic regulation of FGF pathway related genes, i.e. FGFRs, FGFs, and CCND1, could enlighten the way towards biomarker-selected FGFR-targeted therapies. Methods We performed DNA methylation analysis of the encoding genes FGFR1, FGFR2, FGFR3, FGFR4, FGF1-14, FGF16-23, and CCND1 at single CpG site resolution (840 CpG sites) employing The Cancer Genome Research Atlas (TCGA) HNSCC cohort comprising N = 530 tumor tissue and N = 50 normal adjacent tissue samples. We correlated DNA methylation to mRNA expression with regard to human papilloma virus (HPV) and gene amplification status. Moreover, we investigated the correlation of methylation with sensitivity to the selective FGFR inhibitors PD 173074 and AZD4547 in N = 40 HPV(−) HNSCC cell lines. Results We found sequence-contextually nuanced CpG methylation patterns in concordance with epigenetically regulated genes. High methylation levels were predominantly found in the promoter flank and gene body region, while low methylation levels were present in the central promoter region for most of the analyzed CpG sites. FGFRs, FGFs, and CCND1 methylation differed significantly between tumor and normal adjacent tissue and was associated with HPV and gene amplification status. CCND1 promoter methylation correlated with CCND1 amplification. For most of the analyzed CpG sites, methylation levels correlated to mRNA expression in tumor tissue. Furthermore, we found significant correlations of DNA methylation of specific CpG sites with response to the FGFR1/3–selective inhibitors PD 173074 and AZD4547, predominantly within the transcription start site of CCND1. Conclusions Our results suggest an epigenetic regulation of CCND1, FGFRs, and FGFs via DNA methylation in HNSCC and warrants further investigation of DNA methylation as a potential predictive biomarker for response to selective FGFR inhibitors in clinical trials.

scholarly journals The FGF/FGFR System in Breast Cancer: Oncogenic Features and Therapeutic Perspectives

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3029
Author(s):  
Maria Francesca Santolla ◽  
Marcello Maggiolini
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Kinase Inhibitors ◽  
Point Mutations ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Transduction Mechanisms ◽  
Molecular Landscape ◽  
Molecular Aberrations

One of the major challenges in the treatment of breast cancer is the heterogeneous nature of the disease. With multiple subtypes of breast cancer identified, there is an unmet clinical need for the development of therapies particularly for the less tractable subtypes. Several transduction mechanisms are involved in the progression of breast cancer, therefore making the assessment of the molecular landscape that characterizes each patient intricate. Over the last decade, numerous studies have focused on the development of tyrosine kinase inhibitors (TKIs) to target the main pathways dysregulated in breast cancer, however their effectiveness is often limited either by resistance to treatments or the appearance of adverse effects. In this context, the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system represents an emerging transduction pathway and therapeutic target to be fully investigated among the diverse anti-cancer settings in breast cancer. Here, we have recapitulated previous studies dealing with FGFR molecular aberrations, such as the gene amplification, point mutations, and chromosomal translocations that occur in breast cancer. Furthermore, alterations in the FGF/FGFR signaling across the different subtypes of breast cancer have been described. Next, we discussed the functional interplay between the FGF/FGFR axis and important components of the breast tumor microenvironment. Lastly, we pointed out the therapeutic usefulness of FGF/FGFR inhibitors, as revealed by preclinical and clinical models of breast cancer.

Fibroblast growth factor receptor 1 gene amplification in pancreatic ductal adenocarcinoma

2013 ◽  
Vol 63 (2) ◽  
pp. 157-166 ◽  
Author(s):  
Nils C Lehnen ◽  
Anne von Mässenhausen ◽  
Holger Kalthoff ◽  
Hui Zhou ◽  
Tim Glowka ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Fibroblast Growth Factor ◽  
Gene Amplification ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Ductal Adenocarcinoma ◽  
Fibroblast Growth

scholarly journals Aryl extensions of thienopyrimidinones as fibroblast growth factor receptor 1 kinase inhibitors

2011 ◽  
Vol 52 (17) ◽  
pp. 2228-2231 ◽  
Author(s):  
Anil R. Ekkati ◽  
Valsan Mandiyan ◽  
Krishna P. Ravindranathan ◽  
Jae H. Bae ◽  
Joseph Schlessinger ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Kinase Inhibitors ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth

Up-Regulation of miR-195 Expression Leads to Decreased Expression of Basic Fibroblast Growth Factor in CLL Patients Treated with DNA Methylation Inhibitors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3183-3183
Author(s):  
John D. Phillips ◽  
Ioana Pop ◽  
Ken Boucher ◽  
Margaret K. Yu
Keyword(s):  
Dna Methylation ◽  
Growth Factor ◽  
Tumor Suppressor ◽  
Fibroblast Growth Factor ◽  
Basic Fibroblast Growth Factor ◽  
Dna Methyltransferase ◽  
Cpg Island ◽  
Fibroblast Growth ◽  
Substrate Inhibitor ◽  
Dna Methylation Inhibitors

Abstract A higher than age-expected DNA methylation index is predictive for early disease progression in patients with CLL (Yu et al. Leukemia Research 2006). We hypothesized that miRNA expression can also be silenced by promoter hypermethylation in CLL. Thus, methyl pool or DNA methyltransferase inhibitors can upregulate microRNAs with tumor suppressor characteristics by restoring the “normal” pattern of methylation. Results of patients treated with cladribine, a methyl substrate inhibitor, or 5-azacitidine, a DNA methyltransferase inhibitor were compared in 2 separate clinical protocols. The global DNA methylation decreased after treatment with cladribine or 5-azacitidine in 60% of the patients. At the 2006 ASH meeting, we reported on the consistent upregulation of miR-17-3p, miR-21, miR-29a, miR-29b, miR-29c, miR-30e, miR-104, miR-126, miR-128a, miR-130a, miR-141, miR-142-3p, miR-148a, miR-151, miR-199a, miR-199a*, and miR-301 by real-time PCR using the Early Access Human Panel from Applied Biosystems. Data from two patients on the cladribine protocol and 10 patients on the 5-azacitidine protocol were used for statistical analyses. Non-parametric Wilcoxon tests as well as t-tests were performed. Comparisons were made of the responders versus non-responders, and of cladribine versus 5-azacytidine. Since many of the miRNAs showed differences in the cladribine versus 5-azacytidine comparison, a second responder vs non-responder analysis was performed in which the two cladribine subjects were removed. MiR-195 was statistically more upregulated in the cladribine treated responder whereas miR-29c was statistically most upregulated in the 5-azacitidine treated patients (p=0.02). In the patients with global demethylation after treatment, upregulation of microRNA-195 was observed and directly correlated with regional demethylation of the CpG island, confirmed by bisulfite sequencing. Some of the predicted targets of miR-195 include bcl-2, CNOT6L, USP15, PADAH1B1, and ESRRG. MiR-195 may also have tumor suppressor characteristics as it also targets basic fibroblast growth factor (FGF-2), a gene important in CLL angiogenesis. There has been some evidence suggesting FGF-2 is an oncogene. For example, overexpression of FGF-2 isoforms facilitates growth of NIH 3T3 cells in low serum media and also mediates radioresistance of HeLa cells. FGF-2 is also protective against irradiation activation of p53 in the leukemia cells derived from patients with CLL. Although cladribine has been reported to downregulate FGF-2 by inhibiting adenosine deaminase, downregulation of FGF-2 at the transcript and protein levels was also observed in before and after treatment samples from patients treated with 5-azacytidine. We propose an alternative mechanism by which the FGF-2 transcript is degraded after binding to excess miR-195. In patients responsive to treatment with DNA methylation inhibitors, a regional decrease in the methylation status of the CpG island 5′ to miR-195 may lead to increased expression.

Fibroblast growth factor receptor 1 gene amplification in gastric adenocarcinoma

2015 ◽  
Vol 46 (10) ◽  
pp. 1488-1495 ◽  
Author(s):  
Manuel H. Schäfer ◽  
Philipp Lingohr ◽  
Anke Sträßer ◽  
Nils C. Lehnen ◽  
Martin Braun ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Gastric Adenocarcinoma ◽  
Gene Amplification ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth

Identification of Distinct Prognostic Groups: Implications for Patient Selection to Targeted Therapies Among Anti-Endocrine Therapy–Resistant Early Breast Cancers

2019 ◽  
pp. 1-13
Author(s):  
Jane Bayani ◽  
Elizabeth N. Kornaga ◽  
Cheryl Crozier ◽  
Gun Ho Jang ◽  
Lauren Bathurst ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Distant Metastasis ◽  
Targeted Therapies ◽  
Copy Number ◽  
Endocrine Treatment ◽  
Fibroblast Growth ◽  
Breast Cancers ◽  
Free Survival ◽  
Distant Metastasis Free Survival

PURPOSE Hormone receptor–positive breast cancer remains an ongoing therapeutic challenge, despite optimal anti-endocrine therapies. In this study, we assessed the prognostic ability of genomic signatures to identify patients at risk for recurrence after endocrine therapy. Analysis was performed on the basis of an a priori hypothesis related to molecular pathways, which might predict response to existing targeted therapies. PATIENTS AND METHODS A subset of patients from the Tamoxifen Versus Exemestane Adjuvant Multinational trial ( ClinicalTrials.gov identifiers: NCT00279448 and NCT00032136, and NCT00036270) pathology cohort were analyzed to determine the prognostic ability of mutational and copy number aberration biomarkers that represent the cyclin D/cyclin-dependent kinase (CCND/CDK), fibroblast growth factor receptor/fibroblast growth factor (FGFR/FGF), and phosphatidylinositol 3-kinase/protein kinase B (PI3K/ATK) pathways to inform the potential choice of additional therapies to standard endocrine treatment. Copy number analysis and targeted sequencing was performed. Pathways were identified as aberrant if there were copy number aberrations and/or mutations in any of the predetermined pathway genes: CCND1/CCND2/CCND3/CDK4/CDK6, FGFR1/FGFR2/FGFR2/FGFR4, and AKT1/AKT2/PIK3CA/PTEN. RESULTS The 390 of 420 samples that passed quality control were analyzed for distant metastasis–free survival between groups. Patients with no changes in the CCND/CDK pathway experienced a better distant metastasis–free survival (hazard ratio, 1.94; 95% CI, 1.45 to 2.61; P < .001) than those who possessed aberrations. In the FGFR/FGF and PI3K/AKT pathways, a similar outcome was observed (hazard ratio, 1.43 [95% CI, 1.07 to 1.92; P = .017] and 1.34 [95% CI, 1.00 to 1.81; P = .053], respectively). CONCLUSION We show that aberrations of genes in these pathways are independently linked to a higher risk of relapse after endocrine treatment. Improvement of the clinical management of early breast cancers could be made by identifying those for whom current endocrine therapies are sufficient, thus reducing unnecessary treatment, and secondly, by identifying those who are at high risk for recurrence and linking molecular features that drive these cancers to treatment with targeted therapies.

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