GFRA1

Gene Summary

Gene:GFRA1; GDNF family receptor alpha 1
Aliases: GDNFR, RET1L, RETL1, TRNR1, GDNFRA, GFR-ALPHA-1
Location:10q26.11
Summary:Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two structurally related, potent neurotrophic factors that play key roles in the control of neuron survival and differentiation. The protein encoded by this gene is a member of the GDNF receptor family. It is a glycosylphosphatidylinositol(GPI)-linked cell surface receptor for both GDNF and NTN, and mediates activation of the RET tyrosine kinase receptor. This gene is a candidate gene for Hirschsprung disease. Multiple alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Feb 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:GDNF family receptor alpha-1
HPRD
Source:NCBIAccessed: 06 August, 2015

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: GFRA1 (cancer-related)

Liu Z, Zhang J, Gao Y, et al.
Large-scale characterization of DNA methylation changes in human gastric carcinomas with and without metastasis.
Clin Cancer Res. 2014; 20(17):4598-612 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
PURPOSE: Metastasis is the leading cause of death for gastric carcinoma. An epigenetic biomarker panel for predicting gastric carcinoma metastasis could have significant clinical impact on the care of patients with gastric carcinoma. The main purpose of this study is to characterize the methylation differences between gastric carcinomas with and without metastasis.
EXPERIMENTAL DESIGN: Genome-wide DNA methylation profiles between 4 metastatic and 4 nonmetastatic gastric carcinomas and their surgical margins (SM) were analyzed using methylated-CpG island amplification with microarray. The methylation states of 73 candidate genes were further analyzed in patients with gastric carcinoma in a discovery cohort (n=108) using denatured high performance liquid chromatography, bisulfite-sequencing, and MethyLight. The predictive values of potential metastasis-methylation biomarkers were validated in cohorts of patients with gastric carcinoma in China (n=330), Japan (n=129), and Korea (n=153).
RESULTS: The gastric carcinoma genome showed significantly higher proportions of hypomethylation in the promoter and exon-1 regions, as well as increased hypermethylation of intragenic fragments when compared with SMs. Significant differential methylation was validated in the CpG islands of 15 genes (P<0.05) and confirmed using bisulfite sequencing. These genes included BMP3, BNIP3, CDKN2A, ECEL1, ELK1, GFRA1, HOXD10, KCNH1, PSMD10, PTPRT, SIGIRR, SRF, TBX5, TFPI2, and ZNF382. Methylation changes of GFRA1, SRF, and ZNF382 resulted in up- or downregulation of their transcription. Most importantly, the prevalence of GFRA1, SRF, and ZNF382 methylation alterations was consistently and coordinately associated with gastric carcinoma metastasis and the patients' overall survival throughout discovery and validation cohorts in China, Japan, and Korea.
CONCLUSION: Methylation changes of GFRA1, SRF, and ZNF382 may be a potential biomarker set for prediction of gastric carcinoma metastasis.

Naderi E, Mostafaei M, Pourshams A, Mohamadkhani A
Network of microRNAs-mRNAs interactions in pancreatic cancer.
Biomed Res Int. 2014; 2014:534821 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: MicroRNAs are small RNA molecules that regulate the expression of certain genes through interaction with mRNA targets and are mainly involved in human cancer. This study was conducted to make the network of miRNAs-mRNAs interactions in pancreatic cancer as the fourth leading cause of cancer death.
METHODS: 56 miRNAs that were exclusively expressed and 1176 genes that were downregulated or silenced in pancreas cancer were extracted from beforehand investigations. MiRNA-mRNA interactions data analysis and related networks were explored using MAGIA tool and Cytoscape 3 software. Functional annotations of candidate genes in pancreatic cancer were identified by DAVID annotation tool.
RESULTS: This network is made of 217 nodes for mRNA, 15 nodes for miRNA, and 241 edges that show 241 regulations between 15 miRNAs and 217 target genes. The miR-24 was the most significantly powerful miRNA that regulated series of important genes. ACVR2B, GFRA1, and MTHFR were significant target genes were that downregulated.
CONCLUSION: Although the collected previous data seems to be a treasure trove, there was no study simultaneous to analysis of miRNAs and mRNAs interaction. Network of miRNA-mRNA interactions will help to corroborate experimental remarks and could be used to refine miRNA target predictions for developing new therapeutic approaches.

Rusmini M, Griseri P, Matera I, et al.
Expression variability and function of the RET gene in adult peripheral blood mononuclear cells.
J Cell Physiol. 2014; 229(12):2027-37 [PubMed] Related Publications
RET is a gene playing a key role during embryogenesis and in particular during the enteric nervous system development. High levels of RET gene expression are maintained in different human tissues also in adulthood, although their physiological role remains unclear. In particular, collected evidences of a RET contribution in the development and maintenance of the immune system prompted us to investigate its levels of surface expression on peripheral blood mononuclear cells (PBMCs) from adult healthy donors. Despite variability among samples, RET expression was conserved at similar levels in the different immune cell subsets, with higher correlations in similar lymphocyte populations (i.e. CD4(+) and CD8(+) T cells). Conversely, no correlation was found between the amount of RET receptor, the expression of its putative ligands and co-receptors and the genotypes at the RET locus. Moreover, we investigated the RET-associated inflammatory pathways in PBMCs from healthy donors both in resting conditions and upon glial cell derived neurotrophic factor (GDNF) and GPI-linked co-receptors alpha 1 (GFRα1) mediated RET activation. RET mRNA levels positively correlated with the transcript amount of interleukin-8 (IL-8), a cytokine produced by monocytes and macrophages, though we could not demonstrate its direct effect on RET expression by in vitro experiments on THP1 human monocytic cells. These results imply that RET expression might be influenced by either cis- and/or trans-factors, which together would account for its high variability within the general population, and suggest a putative functional role of the RET gene in modulating immune cell responses during inflammation and carcinogenesis.

Evans RL, Pottala JV, Egland KA
Classifying patients for breast cancer by detection of autoantibodies against a panel of conformation-carrying antigens.
Cancer Prev Res (Phila). 2014; 7(5):545-55 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Patients with breast cancer elicit an autoantibody response against cancer proteins, which reflects and amplifies the cellular changes associated with tumorigenesis. Detection of autoantibodies in plasma may provide a minimally invasive mechanism for early detection of breast cancer. To identify cancer proteins that elicit a humoral response, we generated a cDNA library enriched for breast cancer genes that encode membrane and secreted proteins, which are more likely to induce an antibody response compared with intracellular proteins. To generate conformation-carrying antigens that are efficiently recognized by patients' antibodies, a eukaryotic expression strategy was established. Plasma from 200 patients with breast cancer and 200 age-matched healthy controls were measured for autoantibody activity against 20 different antigens designed to have conformational epitopes using ELISA. A conditional logistic regression model was used to select a combination of autoantibody responses against the 20 different antigens to classify patients with breast cancer from healthy controls. The best combination included ANGPTL4, DKK1, GAL1, MUC1, GFRA1, GRN, and LRRC15; however, autoantibody responses against GFRA1, GRN, and LRRC15 were inversely correlated with breast cancer. When the autoantibody responses against the 7 antigens were added to the base model, including age, BMI, race and current smoking status, the assay had the following diagnostic capabilities: c-stat (95% CI), 0.82 (0.78-0.86); sensitivity, 73%; specificity, 76%; and positive likelihood ratio (95% CI), 3.04 (2.34-3.94). The model was calibrated across risk deciles (Hosmer-Lemeshow, P = 0.13) and performed well in specific subtypes of breast cancer including estrogen receptor positive, HER-2 positive, invasive, in situ and tumor sizes >1 cm.

Sato T, Arai E, Kohno T, et al.
DNA methylation profiles at precancerous stages associated with recurrence of lung adenocarcinoma.
PLoS One. 2013; 8(3):e59444 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
The aim of this study was to clarify the significance of DNA methylation alterations at precancerous stages of lung adenocarcinoma. Using single-CpG resolution Infinium array, genome-wide DNA methylation analysis was performed in 36 samples of normal lung tissue obtained from patients without any primary lung tumor, 145 samples of non-cancerous lung tissue (N) obtained from patients with lung adenocarcinomas, and 145 samples of tumorous tissue (T). Stepwise progression of DNA methylation alterations from normal lung tissue to non-cancerous lung tissue obtained from patients with lung adenocarcinomas, and then tumorous tissue samples, was observed at 3,270 CpG sites, suggesting that non-cancerous lung tissue obtained from patients with lung adenocarcinomas was at precancerous stages with DNA methylation alterations. At CpG sites of 2,083 genes, DNA methylation status in samples of non-cancerous lung tissue obtained from patients with lung adenocarcinomas was significantly correlated with recurrence after establishment of lung adenocarcinomas. Among such recurrence-related genes, 28 genes are normally unmethylated (average β-values based on Infinium assay in normal lung tissue samples was less than 0.2) and their DNA hypermethylation at precancerous stages was strengthened during progression to lung adenocarcinomas (Δβ(T-N)>0.1). Among these 28 genes, we focused on 6 for which implications in transcription regulation, apoptosis or cell adhesion had been reported. DNA hypermethylation of the ADCY5, EVX1, GFRA1, PDE9A, and TBX20 genes resulted in reduced mRNA expression in tumorous tissue samples. 5-Aza-2'-deoxycytidine treatment of lung cancer cell lines restored the mRNA expression levels of these 5 genes. Reduced mRNA expression in tumorous tissue samples was significantly correlated with tumor aggressiveness. These data suggest that DNA methylation alterations at precancerous stages determine tumor aggressiveness and outcome through silencing of specific genes.

Krentz AD, Murphy MW, Zhang T, et al.
Interaction between DMRT1 function and genetic background modulates signaling and pluripotency to control tumor susceptibility in the fetal germ line.
Dev Biol. 2013; 377(1):67-78 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Dmrt1 (doublesex and mab-3 related transcription factor (1) is a regulator of testis development in vertebrates that has been implicated in testicular germ cell tumors of mouse and human. In the fetal mouse testis Dmrt1 regulates germ cell pluripotency in a strain-dependent manner. Loss of Dmrt1 in 129Sv strain mice results in a >90% incidence of testicular teratomas, tumors consisting cells of multiple germ layers; by contrast, these tumors have never been observed in Dmrt1 mutants of C57BL/6J (B6) or mixed genetic backgrounds. To further investigate the interaction between Dmrt1 and genetic background we compared mRNA expression in wild type and Dmrt1 mutant fetal testes of 129Sv and B6 mice at embryonic day 15.5 (E15.5), prior to overt tumorigenesis. Loss of Dmrt1 caused misexpression of overlapping but distinct sets of mRNAs in the two strains. The mRNAs that were selectively affected included some that changed expression only in one strain or the other and some that changed in both strains but to a greater degree in one versus the other. In particular, loss of Dmrt1 in 129Sv testes caused a more severe failure to silence regulators of pluripotency than in B6 testes. A number of genes misregulated in 129Sv mutant testes also are misregulated in human testicular germ cell tumors (TGCTs), suggesting similar etiology between germ cell tumors in mouse and man. Expression profiling showed that DMRT1 also regulates pluripotency genes in the fetal ovary, although Dmrt1 mutant females do not develop teratomas. Pathway analysis indicated disruption of several signaling pathways in Dmrt1 mutant fetal testes, including Nodal, Notch, and GDNF. We used a Nanos3-cre knock-in allele to perform conditional gene targeting, testing the GDNF coreceptors Gfra1 and Ret for effects on teratoma susceptibility. Conditional deletion of Gfra1 but not Ret in fetal germ cells of animals outcrossed to 129Sv caused a modest but significant elevation in tumor incidence. Despite some variability in genetic background in these crosses, this result is consistent with previous genetic mapping of teratoma susceptibility loci to the region containing Gfra1. Using Nanos3-cre we also uncovered a strong genetic interaction between Dmrt1 and Nanos3, suggesting parallel functions for these two genes in fetal germ cells. Finally, we used chromatin immunoprecipitation (ChIP-seq) analysis to identify a number of potentially direct DMRT1 targets. This analysis suggested that DMRT1 controls pluripotency via transcriptional repression of Esrrb, Nr5a2/Lrh1, and Sox2. Given the strong evidence for involvement of DMRT1 in human TGCT, the downstream genes and pathways identified in this study provide potentially useful candidates for roles in the human disease.

Maliszewska A, Leandro-Garcia LJ, Castelblanco E, et al.
Differential gene expression of medullary thyroid carcinoma reveals specific markers associated with genetic conditions.
Am J Pathol. 2013; 182(2):350-62 [PubMed] Related Publications
Medullary thyroid carcinoma accounts for 2% to 5% of thyroid malignancies, of which 75% are sporadic and the remaining 25% are hereditary and related to multiple endocrine neoplasia type 2 syndrome. Despite a genotype-phenotype correlation with specific germline RET mutations, knowledge of pathways specifically associated with each mutation and with non-RET-mutated sporadic MTC remains lacking. Gene expression patterns have provided a tool for identifying molecular events related to specific tumor types and to different clinical features that could help identify novel therapeutic targets. Using transcriptional profiling of 49 frozen MTC specimens classified as RET mutation, we identified PROM1, LOXL2, GFRA1, and DKK4 as related to RET(M918T) and GAL as related to RET(634) mutation. An independent series of 19 frozen and 23 formalin-fixed, paraffin-embedded (FFPE) MTCs was used for validation by RT-qPCR. Two tissue microarrays containing 69 MTCs were available for IHC assays. According to pathway enrichment analysis and gene ontology biological processes, genes associated with the MTC(M918T) group were involved mainly in proliferative, cell adhesion, and general malignant metastatic effects and with Wnt, Notch, NFκB, JAK/Stat, and MAPK signaling pathways. Assays based on silencing of PROM1 by siRNAs performed in the MZ-CRC-1 cell line, harboring RET(M918T), caused an increase in apoptotic nuclei, suggesting that PROM1 is necessary for survival of these cells. This is the first report of PROM1 overexpression among primary tumors.

Shaw EJ, Haylock B, Husband D, et al.
Gene expression in oligodendroglial tumors.
Cell Oncol (Dordr). 2011; 34(4):355-67 [PubMed] Related Publications
BACKGROUND: Oligodendroglial tumors with 1p/19q loss are more likely to be chemosensitive and have longer survival than those with intact 1p/19q, but not all respond to chemotherapy, warranting investigation of the biological basis of chemosensitivity.
METHODS: Gene expression profiling was performed using amplified antisense RNA from 28 oligodendroglial tumors treated with chemotherapy [26 serial stereotactic biopsy, 2 resection]. Expression of differentially expressed genes was validated by real-time PCR.
RESULTS: Unsupervised hierarchical clustering showed clustering of multiple samples from the same case in 14/17 cases and identified subgroups associated with tumor grade and 1p/19q status. 176 genes were differentially expressed, 164 being associated with 1p/19q loss (86% not on 1p or 19q). 94 genes differed between responders and non-responders to chemotherapy; 12 were not associated with 1p/19q loss. Significant differential expression was confirmed in 11/13 selected genes. Novel genes associated with response to therapy included SSBP2, GFRA1, FAP and RASD1. IQGAP1, INA, TGIF1, NR2F2 and MYCBP were differentially expressed in oligodendroglial tumors with 1p/19q loss.
CONCLUSION: Gene expression profiling using serial stereotactic biopsies indicated greater homogeneity within tumors than between tumors. Genes associated with 1p/19q status or response were identified warranting further elucidation of their role in oligodendroglial tumors.

Shaw EJ, Haylock B, Husband D, et al.
Gene expression in oligodendroglial tumors.
Anal Cell Pathol (Amst). 2010; 33(2):81-94 [PubMed] Related Publications
BACKGROUND: Oligodendroglial tumors with 1p/19q loss are more likely to be chemosensitive and have longer survival than those with intact 1p/19q, but not all respond to chemotherapy, warranting investigation of the biological basis of chemosensitivity.
METHODS: Gene expression profiling was performed using amplified antisense RNA from 28 oligodendroglial tumors treated with chemotherapy (26 serial stereotactic biopsy, 2 resection). Expression of differentially expressed genes was validated by real-time PCR.
RESULTS: Unsupervised hierarchical clustering showed clustering of multiple samples from the same case in 14/17 cases and identified subgroups associated with tumor grade and 1p/19q status. 176 genes were differentially expressed, 164 being associated with 1p/19q loss (86% not on 1p or 19q). 94 genes differed between responders and non-responders to chemotherapy; 12 were not associated with 1p/19q loss. Significant differential expression was confirmed in 11/13 selected genes. Novel genes associated with response to therapy included SSBP2, GFRA1, FAP and RASD1. IQGAP1, INA, TGIF1, NR2F2 and MYCBP were differentially expressed in oligodendroglial tumors with 1p/19q loss.
CONCLUSION: Gene expression profiling using serial stereotactic biopsies indicated greater homogeneity within tumors than between tumors. Genes associated with 1p/19q status or response were identified warranting further elucidation of their role in oligodendroglial tumors.

Ohshima Y, Yajima I, Takeda K, et al.
c-RET molecule in malignant melanoma from oncogenic RET-carrying transgenic mice and human cell lines.
PLoS One. 2010; 5(4):e10279 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Malignant melanoma is one of the most aggressive cancers and its incidence worldwide has been increasing at a greater rate than that of any other cancer. We previously reported that constitutively activated RFP-RET-carrying transgenic mice (RET-mice) spontaneously develop malignant melanoma. In this study, we showed that expression levels of intrinsic c-Ret, glial cell line-derived neurotrophic factor (Gdnf) and Gdnf receptor alpha 1 (Gfra1) transcripts in malignant melanomas from RET-transgenic mice were significantly upregulated compared with those in benign melanocytic tumors. These results suggest that not only introduced oncogenic RET but also intrinsic c-Ret/Gdnf are involved in murine melanomagenesis in RET-mice. We then showed that c-RET and GDNF transcript expression levels in human malignant melanoma cell lines (HM3KO and MNT-1) were higher than those in primary cultured normal human epithelial melanocytes (NHEM), while GFRa1 transcript expression levels were comparable among NHEM, HM3KO and MNT-1. We next showed c-RET and GFRa1 protein expression in HM3KO cells and GDNF-mediated increased levels of their phosphorylated c-RET tyrosine kinase and signal transduction molecules (ERK and AKT) sited potentially downstream of c-RET. Taken together with the finding of augmented proliferation of HM3KO cells after GDNF stimulation, our results suggest that GDNF-mediated c-RET kinase activation is associated with the pathogenesis of malignant melanoma.

Kim MH, Kim HB, Acharya S, et al.
Ape1/Ref-1 induces glial cell-derived neurotropic factor (GDNF) responsiveness by upregulating GDNF receptor alpha1 expression.
Mol Cell Biol. 2009; 29(8):2264-77 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) dysregulation has been identified in several human tumors and in patients with a variety of neurodegenerative diseases. However, the function of Ape1/Ref-1 is unclear. We show here that Ape1/Ref-1 increases the expression of glial cell-derived neurotropic factor (GDNF) receptor alpha1 (GFRalpha1), a key receptor for GDNF. Expression of Ape1/Ref-1 led to an increase in the GDNF responsiveness in human fibroblast. Ape1/Ref-1 induced GFRalpha1 transcription through enhanced binding of NF-kappaB complexes to the GFRalpha1 promoter. GFRalpha1 levels correlate proportionally with Ape1/Ref-1 in cancer cells. The knockdown of endogenous Ape1/Ref-1 in pancreatic cancer cells markedly suppressed GFRalpha1 expression and invasion in response to GNDF, while overexpression of GFRalpha1 restored invasion. In neuronal cells, the Ape1/Ref-1-mediated increase in GDNF responsiveness not only stimulated neurite outgrowth but also protected the cells from beta-amyloid peptide and oxidative stress. Our results show that Ape1/Ref-1 is a novel physiological regulator of GDNF responsiveness, and they also suggest that Ape1/Ref-1-induced GFRalpha1 expression may play important roles in pancreatic cancer progression and neuronal cell survival.

Sigurdson AJ, Land CE, Bhatti P, et al.
Thyroid nodules, polymorphic variants in DNA repair and RET-related genes, and interaction with ionizing radiation exposure from nuclear tests in Kazakhstan.
Radiat Res. 2009; 171(1):77-88 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Risk factors for thyroid cancer remain largely unknown except for ionizing radiation exposure during childhood and a history of benign thyroid nodules. Because thyroid nodules are more common than thyroid cancers and are associated with thyroid cancer risk, we evaluated several polymorphisms potentially relevant to thyroid tumors and assessed interaction with ionizing radiation exposure to the thyroid gland. Thyroid nodules were detected in 1998 by ultrasound screening of 2997 persons who lived near the Semipalatinsk nuclear test site in Kazakhstan when they were children (1949-1962). Cases with thyroid nodules (n = 907) were frequency matched (1:1) to those without nodules by ethnicity (Kazakh or Russian), gender and age at screening. Thyroid gland radiation doses were estimated from fallout deposition patterns, residence history and diet. We analyzed 23 polymorphisms in 13 genes and assessed interaction with ionizing radiation exposure using likelihood ratio tests (LRT). Elevated thyroid nodule risks were associated with the minor alleles of RET S836S (rs1800862, P = 0.03) and GFRA1 -193C>G (rs not assigned, P = 0.05) and decreased risk with XRCC1 R194W (rs1799782, P trend = 0.03) and TGFB1 T263I (rs1800472, P = 0.009). Similar patterns of association were observed for a small number of papillary thyroid cancers (n = 25). Ionizing radiation exposure to the thyroid gland was associated with significantly increased risk of thyroid nodules (age and gender adjusted excess odds ratio/Gy = 0.30, 95% CI 0.05-0.56), with evidence for interaction by genotype found for XRCC1 R194W (LRT P value = 0.02). Polymorphisms in RET signaling, DNA repair and proliferation genes may be related to risk of thyroid nodules, consistent with some previous reports on thyroid cancer. Borderline support for gene-radiation interaction was found for a variant in XRCC1, a key base excision repair protein. Other pathways such as genes in double-strand break repair, apoptosis and genes related to proliferation should also be pursued.

Esseghir S, Todd SK, Hunt T, et al.
A role for glial cell derived neurotrophic factor induced expression by inflammatory cytokines and RET/GFR alpha 1 receptor up-regulation in breast cancer.
Cancer Res. 2007; 67(24):11732-41 [PubMed] Related Publications
By screening a tissue microarray of invasive breast tumors, we have shown that the receptor tyrosine kinase RET (REarranged during Transfection) and its coreceptor GFR alpha 1 (GDNF receptor family alpha-1) are overexpressed in a subset of estrogen receptor-positive tumors. Germ line-activating oncogenic mutations in RET allow this receptor to signal independently of GFR alpha 1 and its ligand glial cell-derived neurotrophic factor (GDNF) to promote a spectrum of endocrine neoplasias. However, it is not known whether tumor progression can also be driven by receptor overexpression and whether expression of GDNF, as has been suggested for other neurotrophic factors, is regulated in response to the inflammatory microenvironment surrounding many epithelial cancers. Here, we show that GDNF stimulation of RET(+)/GFR alpha 1(+) MCF7 breast cancer cells in vitro enhanced cell proliferation and survival, and promoted cell scattering. Moreover, in tumor xenografts, GDNF expression was found to be up-regulated on the infiltrating endogenous fibroblasts and to a lesser extent by the tumor cells themselves. Finally, the inflammatory cytokines tumor necrosis factor-alpha and interleukin-1 beta, which are involved in tumor promotion and development, were found to act synergistically to up-regulate GDNF expression in both fibroblasts and tumor cells. These data indicate that GDNF can act as an important component of the inflammatory response in breast cancers and that its effects are mediated by both paracrine and autocrine stimulation of tumor cells via signaling through the RET and GFR alpha 1 receptors.

Sawai H, Okada Y, Kazanjian K, et al.
The G691S RET polymorphism increases glial cell line-derived neurotrophic factor-induced pancreatic cancer cell invasion by amplifying mitogen-activated protein kinase signaling.
Cancer Res. 2005; 65(24):11536-44 [PubMed] Related Publications
Mutations of the RET proto-oncogene are responsible for several inherited human diseases and may function as genetic modifiers of the disease. However, the role of RET mutations in pancreatic cancer has not been studied. Expression of the glial cell line-derived neurotrophic factor (GDNF) receptors RET and GDNF family receptor alpha1 (GFRalpha1) in human pancreatic cancer cells was determined by Western blot, immunofluorescence, and flow cytometry. The effect of GDNF on cell proliferation and invasion was assessed. Small interfering RNA and antibodies were used to evaluate the involvement of RET. The G691S RET polymorphism was analyzed by sequencing and restriction analysis. The modifying effect of G691S RET on GDNF-induced invasion and mitogen-activated protein kinase (MAPK) signaling was evaluated. Transfection studies with wild-type and mutated RET determined the functional role of the G691S polymorphism. Pancreatic cancer specimens and matched tissues were analyzed for the presence of the G691S RET polymorphism. GDNF receptors were found on all cell lines. GDNF increased pancreatic cancer cell proliferation and invasion, which was mediated by RET. The effect of GDNF was more profound in cells with the G691S RET polymorphism (P < 0.01). G691S RET correlated with an enhanced activation of the downstream extracellular signal-regulated kinase pathway. Overexpression of G691S RET increased pancreatic cancer cell invasion. The G691S RET polymorphism was also detected in human pancreatic tumors and represented a somatic mutation in some patients. These findings indicate that the G691S RET single nucleotide polymorphism may directly correlate with the aggressive growth of pancreatic cancers and may function as a genetic modifier or even low-penetrance gene.

Kato N, Ji G, Wang Y, et al.
Large-scale search of single nucleotide polymorphisms for hepatocellular carcinoma susceptibility genes in patients with hepatitis C.
Hepatology. 2005; 42(4):846-53 [PubMed] Related Publications
Hepatitis C virus (HCV) infection is a major risk factor for developing hepatocellular carcinoma (HCC). The host genetic factors that are involved in the development of HCC in patients with HCV infection remain to be investigated. To search for single nucleotide polymorphisms (SNPs) in HCC susceptibility genes, 393 SNPs in 171 candidate genes were examined in 188 Japanese patients with chronic HCV infection, including 77 patients with HCC. HCC-related SNPs were then examined in another 188 patients (including 93 patients with HCC) with chronic HCV infection. Haplotype analyses of HCC-related genes were performed in a total of 376 patients. Of the 393 SNPs, 31 SNPs in 29 genes were significantly associated with HCC based on an initial screening (P < .05). Of these 31 SNPs, 3 SNPs of 3 genes (SCYB14, GFRA1, and CRHR2) were significantly associated with HCC in a secondary screening. Haplotype analyses of these 3 genes identified 2 haplotype blocks associated with HCC. In conclusion, these SNPs and haplotypes located in the SCBY14, CRHR2, and GFRA1 genes will be used as markers to identify a subgroup of Japanese patients with chronic HCV infection who are at high risk of developing HCC.

Cebrian A, Lesueur F, Martin S, et al.
Polymorphisms in the initiators of RET (rearranged during transfection) signaling pathway and susceptibility to sporadic medullary thyroid carcinoma.
J Clin Endocrinol Metab. 2005; 90(11):6268-74 [PubMed] Related Publications
CONTEXT: Medullary thyroid carcinoma (MTC) is a characteristic tumor occurring in individuals with multiple endocrine neoplasia type 2 who carry germ-line mutations in RET (rearranged during transfection). However, most MTC occur in individuals without a family history.
OBJECTIVES: The objective of this study was to explore the possibility that susceptibility in these cases results from low penetrance alleles of RET, its coreceptors, and ligands.
DESIGN: We carried out an association study in 135 sporadic MTC (sMTC) patients and 533 controls from the United Kingdom population.
RESULTS AND CONCLUSIONS: We analyzed 33 polymorphisms in all nine genes involved in the glial cell line-derived neurotropic factor receptor-alpha (GFRalpha)-RET complex. This is the first association study in which all genes involved in this complex have been investigated for susceptibility to sMTC. We did not find any association between single nucleotide polymorphisms in the exonic regions of the GFRalpha2, GFRalpha3, GFRalpha4, glial cell line-derived neurotropic factor, neurturin, or persephin genes and risk of developing sMTC. We found a strong association between the disease and specific haplotypes of RET. We not only confirmed the previously described association with G691S and S904S (for heterozygotes: odds ratio, 1.85; range, 1.22-2.82; P = 0.004), but we found a novel protective effect associated with a specific haplotype (odds ratio, 0.39; range, 0.21-0.72; P = 0.005) revealing the existence of different genetic variants in the RET oncogene that either increase or decrease risk of sMTC.

Shimoyama Y, Morikawa Y, Ichihara M, et al.
Identification of human SEP1 as a glial cell line-derived neurotrophic factor-inducible protein and its expression in the nervous system.
Neuroscience. 2003; 121(4):899-906 [PubMed] Related Publications
Glial cell line-derived neurotrophic factor (GDNF) signals through multisubunit receptor complex consisting of RET tyrosine kinase and a glycosylphosphatidylinositol-anchored coreceptor called GDNF family receptor alpha1 (GFRalpha1). In the current study, we cloned a human SEP1 gene as a GDNF-inducible gene using human neuroblastoma cells that express RET and GFRalpha1. The induction of the SEP1 gene showed two peaks at 0.5-2 h and 24-48 h after GDNF stimulation by Northern blotting and quantitative real-time reverse transcriptase polymerase chain reaction. The late induction was also confirmed at protein levels by Western blotting with anti-SEP1 antibody. Immunostaining revealed that the expression of the SEP1 protein was detected in cell body, elongated neurites and growth cone-like structure of neuroblastoma cells treated with GDNF. In addition, we found a high level of SEP1 expression in neurons of the dorsal root and superior cervical ganglia and motor neurons of the spinal cord of mice in which RET is also expressed. SEP1 was co-immunoprecipitated with alpha- and beta-tubulins from the lysate of mouse brain. These results thus suggested that SEP1 is a GDNF-inducible and microtubule-associated protein that may play a role in the nervous system.

Borrego S, Fernández RM, Dziema H, et al.
Evaluation of germline sequence variants of GFRA1, GFRA2, and GFRA3 genes in a cohort of Spanish patients with sporadic medullary thyroid cancer.
Thyroid. 2002; 12(11):1017-22 [PubMed] Related Publications
The etiology of sporadic medullary thyroid carcinoma (sMTC) remains elusive. While germline gain-of-function mutations in the RET proto-oncogene cause hereditary MTC, somatic RET mutations have been described in a variable number of sMTC. So far, S836S of RET, is the only variant whose association with sMTC has been found in several European cohorts. Because RET variants seem to be associated with MTC, it is plausible that variants in genes encoding for RET coreceptors may play a role in the pathogenesis of sMTC. Recently, we described two possible low penetrance susceptibility alleles in the gene encoding RET coreceptor GFRalpha1, -193C > G and 537T > C, in a German series of sMTC. In this study, we have genotyped nine polymorphisms within GFRA1-3 genes for 51 Spanish sMTC, and 100 normal controls. Our results show that no statistical signification was found when Spanish sMTC patients were compared to controls. Taken together with the observations in the German sMTC series, the present findings suggest that GFRA1-193C > G and 537T > C could be in linkage disequilibrium with other loci responsible for the disease with a founder effect in Germany. Alternatively, the combined observations might also suggest that, if indeed the polymorphisms are functional, the effect is small.

Perri P, Longo L, McConville C, et al.
Linkage analysis in families with recurrent neuroblastoma.
Ann N Y Acad Sci. 2002; 963:74-84 [PubMed] Related Publications
Neuroblastoma is a neural crest-derived tumor of childhood with a serious prognosis; only 20% of patients with stage 4 disease survive 5 years from diagnosis. Mechanisms involved in neuroblastoma development are unclear, but the engagement of many neuroblastoma-related gene(s) is suggested by specific chromosomal alterations. Most prominent among these is the amplification of the MYCN oncogene and the deletion of the 1p36 region. Other genetic aberrations have been discovered over the years such as deletions of 11q and 14q and gain of 17q. Although tumor aggressiveness greatly depends on the most frequent genetic abnormalities, to date no neuroblastoma-related gene has been discovered. Neuroblastoma usually occurs sporadically, but 1.5% of all diagnosed cases show familial recurrence with an autosomal dominant inheritance and incomplete penetrance. A comparison between hereditary and sporadic neuroblastomas led Knudson and Strong to gather that the two-hit hypothesis, proposed for retinoblastoma, could be applied to neuroblastoma. To determine if the 1p36 region harbors a predisposition gene for familial neuroblastoma, we carried out linkage analysis at 1p36 loci in two families with recurrent neuroblastoma. Similarly, we analyzed loci of chromosome 16, where a predisposition locus was recently mapped. We also analyzed markers located close to several candidate genes (RET, NF1, GDNF, GFRA1, EDNRB, and EDN3) involved to a different extent in other neurocristopathies. Our findings indicate that the candidate chromosomal regions and genes analyzed are not in linkage with neuroblastoma.

Gil L, Azañedo M, Pollán M, et al.
Genetic analysis of RET, GFR alpha 1 and GDNF genes in Spanish families with multiple endocrine neoplasia type 2A.
Int J Cancer. 2002; 99(2):299-304 [PubMed] Related Publications
Multiple endocrine neoplasia type 2A (MEN 2A) is associated with specific germline missense mutations in the RET proto-oncogene. This locus encodes a receptor tyrosine kinase whose activation requires the formation of a multimeric receptor complex including GDNF as a ligand and GFR alpha 1 as a coreceptor. In order to explore the role of RET, GFR alpha 1 and GDNF genes in the variation of phenotypes observed in MEN2A families, we analysed germline mutations of these genes in 4 unrelated Spanish MEN2A families (23 cases studied). We found 2 novel variants corresponding to a single change in position + 47 (intron 12) of RET and position +22 (intron 7) of GFR alpha 1. Furthermore, we observed strong co-segregation between 2 polymorphisms of RET [G691S (exon 11) and S904S (TCC-TCG, exon 15) (100%, Fisher's exact test, p< 0.001)]. More interestingly, we found that these polymorphisms occurred at a significantly high frequency in patients with age at onset < 20 years old (Kruskal-Wallis's and Fisher's exact test, p = 0.007). These findings suggest that the G691S and S904S variants of RET may somehow play a role on the age of onset of MEN 2A.

Japón MA, Urbano AG, Sáez C, et al.
Glial-derived neurotropic factor and RET gene expression in normal human anterior pituitary cell types and in pituitary tumors.
J Clin Endocrinol Metab. 2002; 87(4):1879-84 [PubMed] Related Publications
Glial-derived neurotropic factor (GDNF) signaling is mediated through a 2-component system consisting of the so-called GDNF receptor-alpha (GFRalpha1), which binds to GDNF. This complex activates the tyrosine kinase receptor RET. In this paper we demonstrate GDNF, GFRalpha1, and RET mRNA and protein expression in the human anterior pituitary gland. Double immunohistochemistry of anterior pituitary sections showed GDNF immunoreactivity in more than 95% of somatotrophs and to a lesser extent in corticotrophs (20%); it was almost absent in the remaining cell types. Also, although more than 95% of somatotrophs were stained for RET, no positive immunostaining could be detected in other cell types. Furthermore, we have looked for GDNF and RET in human pituitary adenomas of various hormonal phenotypes. Strong positive immunostaining was found for c-RET in all of the GH-secreting adenomas screened as well as in 50% of ACTH-producing adenomas. Positive immunostaining for GDNF was found in all of the GH-secreting adenomas and in 10% of the corticotropinomas. Lastly, we found strong positive immunostaining for GFRalpha1 in 90% of the somatotropinomas and 50% of the corticotropinomas as well as in 1 of 8 prolactinomas and 1 of 13 nonfunctioning adenomas. All of the remaining pituitary tumors screened were negative for RET, GDNF, and GFRalpha1. This study indicates that GDNF may well be acting in the regulation of somatotroph cell growth and/or cell function in the normal human anterior pituitary gland. The expression of RET in all of the somatotropinomas and in 50% of the ACTH-producing tumors implies that GDNF and RET could be involved in the pathogenesis of pituitary tumors.

Gimm O, Dziema H, Brown J, et al.
Over-representation of a germline variant in the gene encoding RET co-receptor GFRalpha-1 but not GFRalpha-2 or GFRalpha-3 in cases with sporadic medullary thyroid carcinoma.
Oncogene. 2001; 20(17):2161-70 [PubMed] Related Publications
In contrast to the hereditary form of medullary thyroid carcinoma (MTC), little is known about the etiology of sporadic MTC. Somatic gain-of-function mutations in the RET proto-oncogene, encoding a receptor tyrosine kinase, are found in an average of 40% of sporadic MTC. We analysed 31 sporadic MTC for somatic and germline variants in GFRA1, GFRA2 and GFRA3 which encode the co-receptors of RET. Although there were no somatic mutations in any of the three genes, a sequence variant (-193C>G) in the 5'-UTR of GFRA1 was found in 15% of cases. Three patients were heterozygous (het); another three patients homozygous (hom) for the G variant. The G allele was not observed in 31 race-matched normal controls. Hence, the relative frequency of this variant in sporadic MTC cases and controls differed significantly (P<0.05). Since this variant lies in the 5' UTR, likely at the transcriptional start site, we analysed for differential expression of GFRalpha-1 at the transcript and protein levels. At the mRNA level, GFRA1 was over-expressed in tumors harboring the rare variant (P=0.06). The presence of the G polymorphic allele seemed to be associated with increased expression by immunostaining for GFRalpha-1. Interestingly, cytoplasmic staining was stronger in intensity for het patients and nuclear staining predominant in hom cases. In conclusion, mutation analysis of GFRA1, GFRA2 and GFRA3 revealed over-representation of a rare variant in GFRA1 (-193C>G) in the germline of sporadic MTC cases. Our data suggest that the mechanism is related to over-expression of GFRalpha-1 and differential subcellular compartmentalization but the precise mechanism as to how it acts as a low penetrance susceptibility allele for the development of sporadic MTC remains to be elucidated.

Lindahl M, Poteryaev D, Yu L, et al.
Human glial cell line-derived neurotrophic factor receptor alpha 4 is the receptor for persephin and is predominantly expressed in normal and malignant thyroid medullary cells.
J Biol Chem. 2001; 276(12):9344-51 [PubMed] Related Publications
Glial cell line-derived neurotrophic factor (GDNF) family ligands signal through receptor complex consisting of a glycosylphosphatidylinositol-linked GDNF family receptor (GFR) alpha subunit and the transmembrane receptor tyrosine kinase RET. The inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2), associated with different mutations in RET, is characterized by medullary thyroid carcinoma. GDNF signals via GFRalpha1, neurturin via GFRalpha2, artemin via GFRalpha3, whereas the mammalian GFRalpha receptor for persephin (PSPN) is unknown. Here we characterize the human GFRalpha4 as the ligand-binding subunit required together with RET for PSPN signaling. Human and mouse GFRalpha4 lack the first Cys-rich domain characteristic of other GFRalpha receptors. Unlabeled PSPN displaces (125)I-PSPN from GFRA4-transfected cells, which express endogenous Ret. PSPN can be specifically cross-linked to mammalian GFRalpha4 and Ret, and is able to promote autophosphorylation of Ret in GFRA4-transfected cells. PSPN, but not other GDNF family ligands, promotes the survival of cultured sympathetic neurons microinjected with GFRA4. We identified different splice forms of human GFRA4 mRNA encoding for two glycosylphosphatidylinositol-linked and one putative soluble isoform that were predominantly expressed in the thyroid gland. Overlapping expression of RET and GFRA4 but not other GFRA mRNAs in normal and malignant thyroid medullary cells suggests that GFRalpha4 may restrict the MEN2 syndrome to these cells.

Edström E, Frisk T, Farnebo F, et al.
Expression analysis of RET and the GDNF/GFRalpha-1 and NTN/GFRalpha-2 ligand complexes in pheochromocytomas and paragangliomas.
Int J Mol Med. 2000; 6(4):469-74 [PubMed] Related Publications
Pheochromocytoma and its extra-adrenal counterpart paraganglioma are rare catecholamine producing tumors which usually occur sporadically but may also be a part of neuroendocrine tumor syndromes such as multiple endocrine neoplasia type 2A (MEN 2A). Activating mutations of the RET proto-oncogene which is the underlying cause of MEN 2A, is also seen in approximately 10% of sporadic pheochromocytomas. Glial cell line derived neurotrophic factor (GDNF) and neurturin (NTN) have been shown to function as independent ligands to RET, binding in a complex with the membrane-bound receptors GFRalpha-1 and GFRalpha-2 respectively. Here we have investigated the mRNA expression of RET and its ligand complexes, GDNF/GFRalpha-1 and NTN/GFRalpha-2, in a panel of pheochromocytomas and paragangliomas using mRNA in situ hybridization. RET expression was evident in normal adrenal medulla, and in 13/15 pheochromocytomas, including 5/5 MEN 2A associated tumors, but only in 1/10 paragangliomas. The frequent expression of RET in the pheochromocytomas suggest that this gene might be involved in the tumorigenesis. However, no expression of GDNF/GFRalpha-1 or NTN/GFRalpha-2 could be detected in any of the 25 tumors analyzed, suggesting that these ligand complexes are not important in the development of pheochromocytoma or paraganglioma.

Capes-Davis A, Andrew SD, Hyland VJ, et al.
Glucocorticoids differentially inhibit expression of the RET proto-oncogene.
Gene Expr. 1999; 8(5-6):311-26 [PubMed] Related Publications
The RET proto-oncogene encodes a receptor tyrosine kinase activated by the binding of factors from the glial cell line-derived neurotrophic factor (GDNF) family to receptor-alpha components such as GDNF family receptor alpha-1 (GFR alpha-1). Mutations within the sequence of the RET proto-oncogene are associated with multiple endocrine neoplasia type 2 (MEN 2), an inherited tumor syndrome characterized by the development of medullary thyroid carcinoma (MTC) and other neuroendocrine tumors. Despite Northern analysis showing that RET is expressed in the majority of MTCs, the factors regulating this expression are poorly understood. To address this issue we examined RET expression in response to glucocorticoids in the TT cell line, derived from a metastatic MTC. The synthetic glucocorticoid dexamethasone was found to reduce RET expression at both mRNA and protein levels. This effect was dose responsive and maximal at 24 h. The reduction in RET mRNA was shown to be specific to glucocorticoids and was also seen in a primary MTC culture. Nuclear run-on studies revealed the reduction in steady-state RNA to be due to a decrease in RET mRNA transcription and the effect was shown to be independent of new protein synthesis or RNA stability. Dexamethasone was also found to exert an inhibitory effect upon cell growth, suggesting a potential use for glucocorticoids in the treatment of medullary carcinoma and MEN 2.

Frisk T, Farnebo F, Zedenius J, et al.
Expression of RET and its ligand complexes, GDNF/GFRalpha-1 and NTN/GFRalpha-2, in medullary thyroid carcinomas.
Eur J Endocrinol. 2000; 142(6):643-9 [PubMed] Related Publications
OBJECTIVE: Mutations in the RET proto-oncogene are found in about one third of sporadic medullary thyroid carcinomas (MTCs), mostly affecting codon 918. Glial cell line derived neurotropic factor (GDNF) and its membrane-bound GDNF family receptor alpha (GFRalpha-1), as well as neurturin (NTN) and its membrane-bound receptor GFRalpha-2 form a complex with the RET product, a receptor tyrosine kinase, resulting in downstream signaling to the nucleus.
DESIGN: To elucidate the role of these RET ligands in MTC tumorigenesis, their expression was determined in 15 MTC samples, one papillary thyroid carcinoma (PTC) and three normal thyroid tissue specimens.
METHODS: The mRNA expression of RET, GDNF, GFRalpha-1, NTN and GFRalpha-2 was investigated by mRNA in situ hybridization, and confirmed by reverse transcription-PCR analysis.
RESULTS: None of the five genes was expressed in the normal thyroids or in the PTC. All MTCs showed expression of RET, 13 expressed GDNF, 12 expressed GFRalpha-1 and 9 expressed NTN and GFRalpha-2. In 7 of the tumors RET, GDNF and GFRalpha-1 were expressed at high levels, and in five of these seven tumors NTN and GFRalpha-2 genes were also expressed at high levels. The high level of expression was preferentially seen in tumor cells adjacent to stroma and connective tissue. All MTCs without expression of the RET ligands harbored the RET codon 918 mutation.
CONCLUSIONS: The results suggest that this signaling pathway is important for MTC development, and that it may be activated by expression of the RET ligand complexes by the tumor cells themselves.

Le Hir H, Colucci-D'Amato LG, Charlet-Berguerand N, et al.
High levels of tyrosine phosphorylated proto-ret in sporadic phenochromocytomas.
Cancer Res. 2000; 60(5):1365-70 [PubMed] Related Publications
Pheochromocytomas are tumors originating from chromaffin cells, the large majority of which are sporadic neoplasms. The genetic and molecular events determining their tumorigenesis continue to remain unknown. On the other hand, RET germ-line mutations cause the inheritance of familial tumors in multiple endocrine neoplasia (MEN)-2 diseases, which account for a minority of pheochromocytomas. We investigated the expression of the RET gene in 14 sporadic tumors harboring no activating mutations. A subset of highly RET-expressing tumors (50%) could be distinguished. They showed RET transcript, protein amounts as well as Ret-associated phosphotyrosine levels similar to those measured in MEN-2A-associated pheochromocytomas. We also determined the GDNF and GDNF family receptor alpha (GFRalpha)-1 transcript levels in tumors and in normal tissues. Whereas the GFRalpha-1 transcripts were detected at similar levels in normal tissues and in tumors, GDNF was frequently found expressed in sporadic tumors at levels several times higher than in controls. These results led us to propose the existence of an autocrine or paracrine loop leading to chronic stimulation of the Ret signaling pathway, which could participate in the pathogenesis of a number of sporadic pheochromocytomas.

Yoshimoto K, Tanaka C, Moritani M, et al.
Infrequent detectable somatic mutations of the RET and glial cell line-derived neurotrophic factor (GDNF) genes in human pituitary adenomas.
Endocr J. 1999; 46(1):199-207 [PubMed] Related Publications
RET is a receptor tyrosine kinase expressed in neuroendocrine cells and tumors. RET is activated by a ligand complex comprising glial cell line-derived neurotrophic factor (GDNF) and GDNF receptor-alpha (GDNFR-alpha). Activating mutations of the RET proto-oncogene were found in multiple endocrine neoplasia (MEN) 2 and in sporadic medullary thyroid carcinoma and pheochromocytoma of neuroendocrine origin. Mutations of the RET proto-oncogene and the glial cell line-derived neurotrophic factor (GDNF) gene were examined in human pituitary tumors. No mutations of the RET proto-oncogene including the cysteine-rich region or codon 768 and 918 in the tyrosine kinase domain were detected in 172 human pituitary adenomas either by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) or by PCR-restriction fragment length polymorphism (RFLP). Further, somatic mutations of the GDNF gene in 33 human pituitary adenomas were not detected by PCR-SSCP. One polymorphism of the GDNF gene at codon 145 of TGC or TGT was observed in a prolactinoma. The RET proto-oncogene message was detected in a normal human pituitary gland or 4 of 4 human pituitary adenomas with reverse transcription (RT)-PCR, and in rodent pituitary tumor cell lines with Western blotting. The expression of GDNF gene was detected in 1 of 4 human somatotroph adenomas, 1 of 2 corticotroph adenomas, and 2 of 6 rodent pituitary tumor cell lines with RT-PCR. Based on these, it is concluded that somatic mutations of the RET proto-oncogene or the GDNF gene do not appear to play a major role in the pituitary tumorigenesis in examined tumors.

Gimm O, Gössling A, Marsh DJ, et al.
Mutation and deletion analysis of GFR alpha-1, encoding the co-receptor for the GDNF/RET complex, in human brain tumours.
Br J Cancer. 1999; 80(3-4):383-6 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Glial cell line-derived neurotrophic factor (GDNF) plays a key role in the control of vertebrate neuron survival and differentiation in both the central and peripheral nervous systems. GDNF preferentially binds to GFRalpha-1 which then interacts with the receptor tyrosine kinase RET. We investigated a panel of 36 independent cases of mainly advanced sporadic brain tumours for the presence of mutations in GDNF and GFRalpha-1. No mutations were found in the coding region of GDNF. We identified six previously described GFRalpha-1 polymorphisms, two of which lead to an amino acid change. In 15 of 36 brain tumours, all polymorphic variants appeared to be homozygous. Of these 15 tumours, one also had a rare, apparently homozygous, sequence variant at codon 361. Because of the rarity of the combination of homozygous sequence variants, analysis for hemizygous deletion was pursued in the 15 samples and loss of heterozygosity was found in 11 tumours. Our data suggest that intragenic point mutations of GDNF or GFRalpha-1 are not a common aetiologic event in brain tumours. However, either deletion of GFRalpha-1 and/or nearby genes may contribute to the pathogenesis of these tumours.

Gattei V, Degan M, Rossi FM, et al.
The RET receptor tyrosine kinase, but not its specific ligand, GDNF, is preferentially expressed by acute leukaemias of monocytic phenotype and is up-regulated upon differentiation.
Br J Haematol. 1999; 105(1):225-40 [PubMed] Related Publications
The RET gene product represents the signal-transducing molecule of a surface receptor complex for the glial cell line-derived neurotrophic factor (GDNF), which includes GDNFR-alpha as a ligand-binding component. By a semi-quantitative competitive RT-PCR approach, we have analysed the relative abundances of RET transcripts in blasts purified from 40 acute myeloid leukaemia (AML) cases, revealing significant amounts of RET transcripts in 60% of AML cases (24/40). RT-PCR data was confirmed by immunocytochemical detection of RET protein in leukaemic blasts. The highest RET mRNA levels, almost exclusively confined to FAB M4/M5 AMLs, directly correlated with the presence on leukaemic cells of adhesion molecules and surface structures typically expressed by blasts of monocytic lineage and were inversely associated with the expression of the stem cell antigen CD34. Consistently, differentiation of the monoblastic cell line U937 resulted in an up-regulated expression of RET proto-oncogene, which was maximal upon exposure to agents inducing a more complete monocytic differentiation. Finally, while transcripts specific for GDNF and GDNFR-alpha were never found in leukaemic blasts, stromal cells of the haemopoietic microenvironment expressed, in the absence of RET, significant amounts of both GDNF and GDNFR-alpha. Our results suggest a role for RET in the functional regulation of AMLs through interactions with GDNF- and GDNFR-alpha-producing stromal cells.

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