Fibroblast growth factor receptor 4 gene (FGFR4) 388Arg allele predicts prolonged survival and platinum sensitivity in advanced ovarian cancer (original) (raw)
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Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele
Cancer research, 2002
Expression analysis of genes encoding components of the phosphotyrosine signaling system by cDNA array hybridization revealed elevated levels of FGFR4 transcripts in several mammary carcinoma cell lines. In the FGFR4 gene transcript from MDA-MB-453 mammary carcinoma cells, a G to A conversion was discovered that results in the substitution of glycine by arginine at position 388 in the transmembrane domain of the receptor. The Arg(388) allele was also found in cell lines derived from a variety of other tumor types as well as in the germ-line of cancer patients and healthy individuals. Analysis of three geographically separated groups indicated that it occurs in approximately 50% of the human population. Investigation of the clinical data of 84 breast cancer patients revealed that homo- or heterozygous carriers of the Arg(388) allele had a significantly reduced disease-free survival time (P = 0.01) within a median follow-up of 62 months. Moreover, the FGFR4 Arg(388) allele was associa...
Clinical Cancer Research, 2013
Purpose: To evaluate the prognostic value of fibroblast growth factor receptor 4 (FGFR4) protein expression in patients with advanced-stage, high-grade serous ovarian cancer, delineate the functional role of FGFR4 in ovarian cancer progression, and evaluate the feasibility of targeting FGFR4 in serous ovarian cancer treatment. Experimental Design: Immunolocalization of FGFR4 was conducted on 183 ovarian tumor samples. The collected FGFR4 expression data were correlated with overall survival using Kaplan-Meier and Cox regression analyses. The effects of FGFR4 silencing on ovarian cancer cell growth, survival, invasiveness, apoptosis, and FGF1-mediated signaling pathway activation were evaluated by transfecting cells with FGFR4-specific siRNAs. An orthotopic mouse model was used to evaluate the effect of injection of FGFR4specific siRNAs and FGFR4 trap protein encapsulated in nanoliposomes on ovarian tumor growth in vivo. Results: Overexpression of FGFR4 protein was significantly associated with decreased overall survival durations. FGFR4 silencing significantly decreased the proliferation, survival, and invasiveness and increased apoptosis of ovarian cancer cells. Also, downregulation of FGFR4 significantly abrogated the mitogen-activated protein kinase (MAPK), nuclear factor-kB (NF-kB), and WNT signaling pathways, which are activated by FGF1. Targeting FGFR4 with the FGFR4-specific siRNAs and FGFR4 trap protein significantly decreased ovarian tumor growth in vivo. Conclusions: FGFR4 is a prognostic marker for advanced-stage, high-grade serous ovarian carcinoma. Silencing FGFR4 and inhibiting ligand-receptor binding significantly decrease ovarian tumor growth both in vitro and in vivo, suggesting that targeting ovarian cancer cells with high levels of FGFR4 protein expression is a new therapeutic modality for this disease and will improve survival of it. Clin Cancer Res; 19(4); 809-20. Ó2012 AACR.
Differential effects of polymorphic alleles of FGF receptor 4 on colon cancer growth and metastasis
Cancer research, 2012
A gly 388 arg polymorphism (rs351855) in the transmembrane domain of the fibroblast growth factor receptor (FGFR4) is associated with increased risk, staging, and metastasis in several different types of cancer. To specifically assess the impact of the polymorphic FGFR4 in colorectal cancer (CRC), we engineered CRC cell lines with distinct endogenous expression patterns to overexpress either the FGFR4 gly or FGFR4 arg alleles. The biologic analyses revealed an oncogenic importance for both polymorphic alleles, but FGFR4 gly was the stronger inducer of tumor growth, whereas FGFR4 arg was the stronger inducer of migration. An evaluation of clinical specimens revealed that FGFR4 was upregulated in 20/71 patients independent of gly 388 arg status. There was no correlation between the presence of an FGFR4 arg allele and CRC or polyp risk in 3,471 participants of the CORSA study. However, among 182 patients with CRC, FGFR4 arg -carriers had a fivefold higher risk of tumors that were stage II or greater. Together, our results established that both allelic forms of FGFR4 exert an oncogenic impact and may serve equally well as therapeutic targets in CRC. One important implication of our findings is that FGFR4 argcarriers are at a higher risk for more aggressive tumors and therefore may profit from early detection measures. Cancer Res; 72(22); 5767-77. Ó2012 AACR.
G388R mutation of the FGFR4 gene is not relevant to breast cancer prognosis
British journal of cancer, 2004
This study screened large cohorts of node-positive and node-negative breast cancer patients to determine whether the G388R mutation of the FGFR4 gene is a useful prognostic marker for breast cancer as reported by Bange et al in 2002. Node-positive (n=139) and node-negative (n=95) breast cancer cohorts selected for mutation screening were followed up for median periods of 89 and 87 months, respectively. PCR - RFLP analysis was modified to facilitate molecular screening. Curves for disease-free survival were plotted according to the Kaplan - Meier method, and a log-rank test was used for comparisons between groups. Three other nonparametric linear rank-tests particularly suitable for investigating possible relations between G388R mutation and early cancer progression were also used. Kaplan - Meier analysis based on any of the four nonparametric linear rank tests performed for node-positive and node-negative patients was not indicative of disease-free survival time. G388R mutation of t...
British Journal of Cancer, 2014
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 ¼ 1.02-1.09, P ¼ 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.
FGFR1 Amplification Drives Endocrine Therapy Resistance and Is a Therapeutic Target in Breast Cancer
Cancer Research, 2010
Amplification of FGFR1 occurs in approximately 10% of breast cancers and is associated with poor prognosis. However, it is uncertain whether over-expression of FGFR1 is causally linked to the poor prognosis of amplified cancers. Here, we show that FGFR1 over-expression is robustly associated with FGFR1 amplification in two independent series of breast cancers. Breast cancer cell lines with FGFR1 over-expression, and amplification, show enhanced ligand dependent signalling, with increased activation of the MAPK and PI3K-AKT signalling pathways in response to FGF2, but also show basal ligand independent signalling, and are dependent on FGFR signalling for anchorage independent growth. FGFR1 amplified cell lines demonstrate resistance to 4-OH-Tamoxifen, that is reversed by siRNA silencing of FGFR1, suggesting that FGFR1 overexpression also promotes endocrine therapy resistance. FGFR1 signalling suppresses progesterone receptor (PR) expression in vitro and likewise amplified cancers are frequently PR negative, identifying a potential biomarker for FGFR1 activity. Furthermore, we show that amplified cancers have a high proliferative rate assessed by Ki67 staining, and that FGFR1 amplification is found in 16-27% of luminal B type breast cancers. Our data suggests that amplification and overexpression of FGFR1 may be a major contributor to poor prognosis in luminal type breast cancers, driving anchorage independent proliferation and endocrine therapy resistance.
FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease
Journal of Clinical Investigation, 2020
Conflict of interest: CMP is an equity stock holder, consultant, and Board of Directors member of BioClassifier LLC and GeneCentric Therapeutics. CMP and JSP are also listed as inventors on patent applications for the Breast Cancer PAM50 Subtyping assay. AP is a consultant/advisory board member for NanoString Technologies. AL is on the Advisory Board and consults for Novartis, Pfizer, Roche/Genentech, Eisai, and Celgene, and as a clinician is involved in clinical research managed by the
Twin Research and Human Genetics, 2009
Fibroblast growth factor (FGF)-2 (basic) is a potent angiogenic molecule involved in tumour progression, and is one of several growth factors with a central role in ovarian carcinogenesis. We hypothesised that common single nucleotide polymorphisms (SNPs) in the FGF2 gene may alter angiogenic potential and thereby susceptibility to ovarian cancer. We analysed 25 FGF2 tgSNPs using five independent study populations from the United States and Australia. Analysis was restricted to non-Hispanic White women with serous ovarian carcinoma (1269 cases and 2829 controls). There were no statistically significant associations between any FGF2 SNPs and ovarian cancer risk. There were two nominally statistically significant associations between heterozygosity for two FGF2 SNPs (rs308379 and rs308447; p<0.05) and serous ovarian cancer risk in the combined dataset, but rare homozygous estimates did not achieve statistical significance, nor were they consistent with the log additive model of inheritance. Overall genetic variation in FGF2 does not appear to play a role in susceptibility to ovarian cancer.