EPHA5

Gene Summary

Gene:EPHA5; EPH receptor A5
Aliases: EK7, CEK7, EHK1, HEK7, EHK-1, TYRO4
Location:4q13.1-q13.2
Summary:This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Aug 2013]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:ephrin type-A receptor 5
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: EPHA5 (cancer-related)

Zhang M, Luo SC
Gene expression profiling of epithelial ovarian cancer reveals key genes and pathways associated with chemotherapy resistance.
Genet Mol Res. 2016; 15(1) [PubMed] Related Publications
The aim of this study is to analyze gene expression data to identify key genes and pathways associated with resistance to platinum-based chemotherapy in epithelial ovarian cancer (EOC) and to improve clinical treatment strategies. The gene expression data set was downloaded from Gene Expression Omnibus and included 12 chemotherapy-resistant EOC samples and 16 chemotherapy-sensitive EOC samples. A differential analysis was performed to screen out differentially expressed genes (DEGs). A functional enrichment analysis was conducted for the DEGs using the database for annotation, visualization, and integration discovery. A protein-protein interaction (PPI) network was constructed with information from the human protein reference database. Pathway-pathway interactions were determined with a test based on the hypergeometric distribution. A total of 1564 DEGs were identified in chemotherapy-sensitive EOC, including 654 upregulated genes and 910 downregulated genes. The top three upregulated genes were HIST1H3G, AKT3, and RTN3, while the top three downregulated genes were NBLA00301, TRIM62, and EPHA5. A Gene Ontology enrichment analysis showed that cell adhesion, biological adhesion, and intracellular signaling cascades were significantly enriched in the DEGs. A KEGG pathway enrichment analysis revealed that the calcium, mitogen-activated protein kinase, and B cell receptor signaling pathways were significantly over-represented in the DEGs. A PPI network containing 101 interactions was acquired. The top three hub genes were RAC1, CAV1, and BCL2. Five modules were identified from the PPI network. Taken together, these findings could advance the understanding of the molecular mechanisms underlying intrinsic chemotherapy resistance in EOC.

Sepulveda JL, Gutierrez-Pajares JL, Luna A, et al.
High-definition CpG methylation of novel genes in gastric carcinogenesis identified by next-generation sequencing.
Mod Pathol. 2016; 29(2):182-93 [PubMed] Related Publications
Gastric cancers are the most frequent gastric malignancy and usually arise in the sequence of Helicobacter pylori-associated chronic gastritis. CpG methylation is a central mechanism of epigenetic gene regulation affecting cancer-related genes, and occurs early in gastric carcinogenesis. DNA samples from non-metaplastic gastric mucosa with variable levels of gastritis (non-metaplastic mucosa), intestinal metaplasia, or gastric cancer were screened with methylation arrays for CpG methylation of cancer-related genes and 30 gene targets were further characterized by high-definition bisulfite next-generation sequencing. In addition, data from The Cancer Genome Atlas were analyzed for correlation of methylation with gene expression. Overall, 13 genes had significantly increased CpG methylation in gastric cancer vs non-metaplastic mucosa (BRINP1, CDH11, CHFR, EPHA5, EPHA7, FGF2, FLI1, GALR1, HS3ST2, PDGFRA, SEZ6L, SGCE, and SNRPN). Further, most of these genes had corresponding reduced expression levels in gastric cancer compared with intestinal metaplasia, including novel hypermethylated genes in gastric cancer (FLI1, GALR1, SGCE, and SNRPN), suggesting that they may regulate neoplastic transformation from non-malignant intestinal metaplasia to cancer. Our data suggest a tumor-suppressor role for FLI1 in gastric cancer, consistent with recently reported data in breast cancer. For the genes with strongest methylation/expression correlation, namely FLI1, the expression was lowest in microsatellite-unstable tumors compared with other gastric cancer molecular subtypes. Importantly, reduced expression of hypermethylated BRINP1 and SGCE was significantly associated with favorable survival in gastric cancer. In summary, we report novel methylation gene targets that may have functional roles in discrete stages of gastric carcinogenesis and may serve as biomarkers for diagnosis and prognosis of gastric cancer.

Boora GK, Kanwar R, Kulkarni AA, et al.
Testing of candidate single nucleotide variants associated with paclitaxel neuropathy in the trial NCCTG N08C1 (Alliance).
Cancer Med. 2016; 5(4):631-9 [PubMed] Free Access to Full Article Related Publications
Paclitaxel-induced peripheral neuropathy (PIPN) cannot be predicted from clinical parameters and might have a pharmacogenomic basis. Previous studies identified single nucleotide variants (SNV) associated with PIPN. However, only a subset of findings has been confirmed to date in more than one study, suggesting a need for further re-testing and validation in additional clinical cohorts. Candidate PIPN-associated SNVs were identified from the literature. SNVs were retested in 119 patients selected by extreme phenotyping from 269 in NCCTG N08C1 (Alliance) as previously reported. SNV genotyping was performed by a combination of short-read sequencing analysis and Taqman PCR. These 22 candidate PIPN SNVs were genotyped. Two of these, rs7349683 in the EPHA5 and rs3213619 in ABCB1 were found to be significantly associated with PIPN with an Odds ratios OR = 2.07 (P = 0.02) and OR = 0.12 (P = 0.03), respectively. In addition, three SNVs showed a trend toward a risk- or protective effect that was consistent with previous reports. The rs10509681 and rs11572080 in the gene CYP2C8*3 showed risk effect with an OR = 1.49 and rs1056836 in CYP1B1 showed a protective effect with an OR = 0.66. None of the other results supported the previously reported associations, including some SNVs displaying an opposite direction of effect from previous reports, including rs1058930 in CYP2C8, rs17222723 and rs8187710 in ABCC2, rs10771973 in FGD4, rs16916932 in CACNB2 and rs16948748 in PITPNA. Alliance N08C1 validated or supported a minority of previously reported SNV-PIPN associations. Associations previously reported by multiple studies appeared to have a higher likelihood to be validated by Alliance N08C1.

Quinn AM, Hickson N, Adaway M, et al.
Diagnostic Mutation Profiling and Validation of Non-Small-Cell Lung Cancer Small Biopsy Samples using a High Throughput Platform.
J Thorac Oncol. 2015; 10(5):784-92 [PubMed] Related Publications
BACKGROUND: A single platform designed for the synchronous screening of multiple mutations can potentially enable molecular profiling in samples of limited tumor tissue. This approach is ideal for the assessment of advanced non-small-cell lung cancer (NSCLC) diagnostic specimens, which often comprise small biopsies. Therefore, we aimed in this study to validate the mass spectrometry-based Sequenom LungCarta panel and MassARRAY platform using DNA extracted from a single 5 μM formalin-fixed paraffin-embedded tissue section.
METHODS: Mutations, including those with an equivocal spectrum, detected in 90 cases of NSCLC (72 lung biopsies, 13 metastatic tissue biopsies, three resections, and two cytology samples) were validated by a combination of standard sequencing techniques, immunohistochemical staining for p53 protein, and next-generation sequencing with the TruSight Tumor panel.
RESULTS: Fifty-five mutations were diagnosed in 47 cases (52%) in the following genes: TP53 (22), KRAS (15), EGFR (5), MET (3), PIK3CA (3), STK11 (2), NRF-2 (2), EPHA5 (1), EPHA3 (1), and MAP2K1 (1). Of the 90 samples, one failed testing due to poor quality DNA. An additional 7 TP53 mutations were detected by next-generation sequencing, which facilitated the interpretation of p53 immunohistochemistry but required 5 × 10 μM tumor sections per sample tested.
CONCLUSIONS: The LungCarta panel is a sensitive method of screening for multiple alterations (214 mutations across 26 genes) and which optimizes the use of limited amounts of tumor DNA isolated from small specimens.

Li S, Zhu Y, Ma C, et al.
Downregulation of EphA5 by promoter methylation in human prostate cancer.
BMC Cancer. 2015; 15:18 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: EphA5 is a member of the Eph/ephrin family and plays a critical role in the regulation of carcinogenesis. A significant reduction of EphA5 transcripts in high-grade prostate cancer tissue was shown using a transcriptomic analysis, compared to the low-grade prostate cancer tissue. As less is known about the mechanism of EphA5 downregulation and the function of EphA5, here we investigated the expression and an epigenetic change of EphA5 in prostate cancer and determined if these findings were correlated with clinicopathologic characteristics of prostate cancer.
METHODS: Seven prostate cell lines (RWPE-1, LNCap, LNCap-LN3, CWR22rv-1, PC-3, PC-3M-LN4, and DU145), thirty-nine BPH, twenty-two primary prostate carcinomas, twenty-three paired noncancerous and cancerous prostate tissues were examined via qRT-PCR, methylation-specific PCR, bisulfite sequencing, immunohistochemistry and western blotting. The role of EphA5 in prostate cancer cell migration and invasion was examined by wound healing and transwell assay.
RESULTS: Downregulation or loss of EphA5 mRNA or protein expression was detected in 28 of 45 (62.2%) prostate carcinomas, 2 of 39 (5.1%) hyperplasias, and all 6 prostate cancer cell lines. Methylation of the EphA5 promoter region was present in 32 of 45 (71.1%) carcinoma samples, 3 of 39 (7.7%) hyperplasias, and the 6 prostate cancer cell lines. Among 23 paired prostate carcinoma tissues, 16 tumor samples exhibited the hypermethylation of EphA5, and 15 of these 16 specimens (93.8%) shown the downregulation of EphA5 expression than that of their respectively matched noncancerous samples. Immunostaining analysis demonstrated that the EphA5 protein was absent or down-regulated in 10 of 13 (76.9%) available carcinoma samples, and 8 of these 10 samples (80.0%) exhibited hypermethylation. The frequency of EphA5 methylation was higher in cancer patients with an elevated Gleason score or T3-T4 staging. Following the treatment of 6 prostate cancer cell lines with 5-aza-2'-deoxycytidine, the levels of EphA5 mRNA were significantly increased. Prostate cancer cells invasion and migration were significantly suppressed by ectopic expression of EphA5 in vitro.
CONCLUSION: Our study provides evidence that EphA5 is a potential target for epigenetic silencing in primary prostate cancer and is a potentially valuable prognosis predictor and thereapeutic marker for prostate cancer.

Jour G, Scarborough JD, Jones RL, et al.
Molecular profiling of soft tissue sarcomas using next-generation sequencing: a pilot study toward precision therapeutics.
Hum Pathol. 2014; 45(8):1563-71 [PubMed] Related Publications
Next-generation sequencing (NGS) can provide in-depth detection of numerous gene alterations. To date, there are very few reports describing the use of this technique in soft tissue sarcomas. Herein, we aim to test the utility of NGS in identifying targetable mutations in these tumors. NGS was performed using a clinically validated multiplexed gene sequencing panel interrogating the full coding sequence of 194 cancer-related genes. A custom bioinformatics pipeline was developed to detect all classes of mutations directly from the NGS data, including single-nucleotide variants, small insertions and deletions, copy number variation, and complex structural variations. Twenty-five soft tissue sarcomas were analyzed; 18 of these patients had metastatic disease and 7 primary locally advanced tumors. Targetable mutations for which clinical trials are available were identified in 60% of the cases. MAP2K4, AURKA, AURKB, and c-MYC amplification were recurrent events in leiomyosarcomas. Frequent non-targetable variants included copy losses of the TP53 (24%), PTEN (16%), and CDKN2A (20%). Additional frameshift mutations, deletion mutations, and single-nucleotide variants involving numerous genes, including RB1, NOTCH1, PIK3CA, PDGFRB, EPHA5, KDM6A, NF1, and FLT4 genes, were also identified. NGS is useful in identifying targetable mutations in soft tissue sarcomas that can serve as a rationale for inclusion of patients with advanced disease in ongoing clinical trials and allow for better risk stratification.

Madden SF, Clarke C, Gaule P, et al.
BreastMark: an integrated approach to mining publicly available transcriptomic datasets relating to breast cancer outcome.
Breast Cancer Res. 2013; 15(4):R52 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Breast cancer is a complex heterogeneous disease for which a substantial resource of transcriptomic data is available. Gene expression data have facilitated the division of breast cancer into, at least, five molecular subtypes, namely luminal A, luminal B, HER2, normal-like and basal. Once identified, breast cancer subtypes can inform clinical decisions surrounding patient treatment and prognosis. Indeed, it is important to identify patients at risk of developing aggressive disease so as to tailor the level of clinical intervention.
METHODS: We have developed a user-friendly, web-based system to allow the evaluation of genes/microRNAs (miRNAs) that are significantly associated with survival in breast cancer and its molecular subtypes. The algorithm combines gene expression data from multiple microarray experiments which frequently also contain miRNA expression information, and detailed clinical data to correlate outcome with gene/miRNA expression levels. This algorithm integrates gene expression and survival data from 26 datasets on 12 different microarray platforms corresponding to approximately 17,000 genes in up to 4,738 samples. In addition, the prognostic potential of 341 miRNAs can be analysed.
RESULTS: We demonstrated the robustness of our approach in comparison to two commercially available prognostic tests, oncotype DX and MammaPrint. Our algorithm complements these prognostic tests and is consistent with their findings. In addition, BreastMark can act as a powerful reductionist approach to these more complex gene signatures, eliminating superfluous genes, potentially reducing the cost and complexity of these multi-index assays. Known miRNA prognostic markers, mir-205 and mir-93, were used to confirm the prognostic value of this tool in a miRNA setting. We also applied the algorithm to examine expression of 58 receptor tyrosine kinases in the basal-like subtype, identifying six receptor tyrosine kinases associated with poor disease-free survival and/or overall survival (EPHA5, FGFR1, FGFR3, VEGFR1, PDGFRβ, and TIE1). A web application for using this algorithm is currently available.
CONCLUSIONS: BreastMark is a powerful tool for examining putative gene/miRNA prognostic markers in breast cancer. The value of this tool will be in the preliminary assessment of putative biomarkers in breast cancer. It will be of particular use to research groups with limited bioinformatics facilities.

Leandro-García LJ, Inglada-Pérez L, Pita G, et al.
Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy.
J Med Genet. 2013; 50(9):599-605 [PubMed] Related Publications
BACKGROUND: Peripheral neuropathy is the dose limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat solid tumours. This toxicity exhibits great inter-individual variability of unknown origin. The present study aimed to identify genetic variants associated with paclitaxel induced neuropathy via a whole genome approach.
METHODS: A genome-wide association study (GWAS) was performed in 144 white European patients uniformly treated with paclitaxel/carboplatin and for whom detailed data on neuropathy was available. Per allele single nucleotide polymorphism (SNP) associations were assessed by Cox regression, modelling the cumulative dose of paclitaxel up to the development of grade 2 sensory neuropathy.
RESULTS: The strongest evidence of association was observed for the ephrin type A receptor 4 (EPHA4) locus (rs17348202, p=1.0×10(-6)), and EPHA6 and EPHA5 were among the top 25 and 50 hits (rs301927, p=3.4×10(-5) and rs1159057, p=6.8×10(-5)), respectively. A meta-analysis of EPHA5-rs7349683, the top marker for paclitaxel induced neuropathy in a previous GWAS (r(2)=0.79 with rs1159057), gave a hazard ratio (HR) estimate of 1.68 (p=1.4×10(-9)). Meta-analysis of the second hit of this GWAS, XKR4-rs4737264, gave a HR of 1.71 (p=3.1×10(-8)). Imputed SNPs at LIMK2 locus were also strongly associated with this toxicity (HR=2.78, p=2.0×10(-7)).
CONCLUSIONS: This study provides independent support of EPHA5-rs7349683 and XKR4-rs4737264 as the first markers of risk of paclitaxel induced neuropathy. In addition, it suggests that other EPHA genes also involved in axonal guidance and repair following neural injury, as well as LIMK2 locus, may play an important role in the development of this toxicity. The identified SNPs could form the basis for individualised paclitaxel chemotherapy.

DiNardo CD, Gharibyan V, Yang H, et al.
Impact of aberrant DNA methylation patterns including CYP1B1 methylation in adolescents and young adults with acute lymphocytic leukemia.
Am J Hematol. 2013; 88(9):784-9 [PubMed] Free Access to Full Article Related Publications
Aberrant promoter DNA methylation is a well-described mechanism of leukemogenesis within hematologic malignancies, including acute lymphoblastic leukemia (ALL). However, the importance of methylation patterns among the adolescent and young adult (AYA) ALL population has not been well established. DNA methylation of 18 candidate genes in 33 AYA ALL patients was analyzed at diagnosis and during treatment, to evaluate the frequency and clinical relevance of aberrant methylation in an AYA population treated on a uniform therapeutic regimen. Of 16 informative genes, there was a median of 6 methylated genes per AYA ALL patient. Correlations were identified between increasing number of methylated genes with male sex (P = 0.04), increased white blood cell (WBC) count (P = 0.04) and increased bone-marrow blast percentage (P = 0.04). Increasing age was associated with EPHA5 methylation (P = 0.05). Overall, patients experienced favorable outcomes with median survival that was not reached. On univariate analysis, methylation of CYP1B1 was associated with worse overall survival (HR 10.7, 95% CI 1.3-87.6, P = 0.03), disease-free survival (HR 3.7, 95% CI 1.1-9.2, P = 0.04) and correlated with decreased CYP1B1 gene expression. A significant incidence of methylation within the AYA ALL population was identified, with increased methylation associated with distinct clinicopathologic features including male gender and elevated WBC count. Our results suggest aberrant methylation among AYA patients is frequent, and may provide a common pathogenic mechanism. The inferior outcome identified with methylation of the cytochrome p450 gene CYP1B1, an enzyme involved in drug metabolism and steroid synthesis, warrants further investigation.

Jiao X, Hooper SD, Djureinovic T, et al.
Gene rearrangements in hormone receptor negative breast cancers revealed by mate pair sequencing.
BMC Genomics. 2013; 14:165 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Chromosomal rearrangements in the form of deletions, insertions, inversions and translocations are frequently observed in breast cancer genomes, and a subset of these rearrangements may play a crucial role in tumorigenesis. To identify novel somatic chromosomal rearrangements, we determined the genome structures of 15 hormone-receptor negative breast tumors by long-insert mate pair massively parallel sequencing.
RESULTS: We identified and validated 40 somatic structural alterations, including the recurring fusion between genes DDX10 and SKA3 and translocations involving the EPHA5 gene. Other rearrangements were found to affect genes in pathways involved in epigenetic regulation, mitosis and signal transduction, underscoring their potential role in breast tumorigenesis. RNA interference-mediated suppression of five candidate genes (DDX10, SKA3, EPHA5, CLTC and TNIK) led to inhibition of breast cancer cell growth. Moreover, downregulation of DDX10 in breast cancer cells lead to an increased frequency of apoptotic nuclear morphology.
CONCLUSIONS: Using whole genome mate pair sequencing and RNA interference assays, we have discovered a number of novel gene rearrangements in breast cancer genomes and identified DDX10, SKA3, EPHA5, CLTC and TNIK as potential cancer genes with impact on the growth and proliferation of breast cancer cells.

Almog N, Ma L, Schwager C, et al.
Consensus micro RNAs governing the switch of dormant tumors to the fast-growing angiogenic phenotype.
PLoS One. 2012; 7(8):e44001 [PubMed] Free Access to Full Article Related Publications
Tumor dormancy refers to a critical stage in cancer development in which tumor cells remain occult for a prolonged period of time until they eventually progress and become clinically apparent. We previously showed that the switch of dormant tumors to fast-growth is angiogenesis dependent and requires a stable transcriptional reprogramming in tumor cells. Considering microRNAs (miRs) as master regulators of transcriptome, we sought to investigate their role in the control of tumor dormancy. We report here the identification of a consensus set of 19 miRs that govern the phenotypic switch of human dormant breast carcinoma, glioblastoma, osteosarcoma, and liposarcoma tumors to fast-growth. Loss of expression of dormancy-associated miRs (DmiRs, 16/19) was the prevailing regulation pattern correlating with the switch of dormant tumors to fast-growth. The expression pattern of two DmiRs (miR-580 and 190) was confirmed to correlate with disease stage in human glioma specimens. Reconstitution of a single DmiR (miR-580, 588 or 190) led to phenotypic reversal of fast-growing angiogenic tumors towards prolonged tumor dormancy. Of note, 60% of angiogenic glioblastoma and 100% of angiogenic osteosarcoma over-expressing miR190 remained dormant during the entire observation period of ∼ 120 days. Next, the ability of DmiRs to regulate angiogenesis and dormancy-associated genes was evaluated. Transcriptional reprogramming of tumors via DmiR-580, 588 or 190 over-expression resulted in downregulation of pro-angiogenic factors such as TIMP-3, bFGF and TGFalpha. In addition, a G-CSF independent downregulation of Bv8 was found as a common target of all three DmiRs and correlated with decreased tumor recruitment of bone marrow-derived CD11b+ Gr-1+ myeloid cells. In contrast, antiangiogenic and dormancy promoting pathways such as EphA5 and Angiomotin were upregulated in DmiR over-expressing tumors. This work suggests novel means to reverse the malignant tumor phenotype into an asymptomatic dormant state and may provide promising targets for early detection or prevention of cancer.

Baldwin RM, Owzar K, Zembutsu H, et al.
A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101.
Clin Cancer Res. 2012; 18(18):5099-109 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Sensory peripheral neuropathy is a common and sometimes debilitating toxicity associated with paclitaxel therapy. This study aims to identify genetic risk factors for the development of this toxicity.
EXPERIMENTAL DESIGN: A prospective pharmacogenetic analysis of patients with primary breast cancer, randomized to the paclitaxel arm of CALGB 40101, was used to identify genetic predictors of the onset and severity of sensory peripheral neuropathy. A genome-wide association study in 855 subjects of European ancestry was conducted and findings were replicated in additional European (n = 154) and African American (n = 117) subjects.
RESULTS: A single nucleotide polymorphism in FGD4 was associated with the onset of sensory peripheral neuropathy in the discovery cohort [rs10771973; HR, 1.57; 95% confidence interval (CI), 1.30-1.91; P = 2.6 × 10(-6)] and in a European (HR, 1.72; 95% CI, 1.06-2.80; P = 0.013) and African American (HR, 1.93; 95% CI, 1.13-3.28; P = 6.7 × 10(-3)) replication cohort. There is also evidence that markers in additional genes, including EPHA5 (rs7349683) and FZD3 (rs10771973), were associated with the onset or severity of paclitaxel-induced sensory peripheral neuropathy.
CONCLUSIONS: A genome-wide association study has identified novel genetic markers of paclitaxel-induced sensory peripheral neuropathy, including a common polymorphism in FGD4, a congenital peripheral neuropathy gene. These findings suggest that genetic variation may contribute to variation in development of this toxicity. Validation of these findings may allow for the identification of patients at increased risk of peripheral neuropathy and inform the use of an alternative to paclitaxel and/or the clinical management of this toxicity.

Kober P, Bujko M, Olędzki J, et al.
Methyl-CpG binding column-based identification of nine genes hypermethylated in colorectal cancer.
Mol Carcinog. 2011; 50(11):846-56 [PubMed] Related Publications
DNA methylation is an epigenetic event that plays a role in gene expression regulation. Alterations in DNA methylation contribute to cancer development and progression. The aim of this study was to identify gene promoters aberrantly methylated in colorectal tumor tissue in comparison to normal colonic mucosa. Analyses were performed on two pooled DNA samples: from normal and cancerous tissue obtained from CRC patients. DNA was fractionated according to methylation degree with the use of affinity column containing methyl-CpG binding domain. To identify novel hypermethylated gene promoters, methylated DNA from normal and from cancerous tissues were analyzed with the use of promoter microarrays. We identified nine novel genes hypermethylated in colorectal cancer. The frequency of their promoter methylation was assessed in the larger group of patients (n = 77): KCNK12 (methylated in 41% of CRC patients), GPR101 (40%), CDH2 (45%), BARX1 (56%), CNTFR (22%), SYT6 (64%), SMO (21%), EPHA5 (43%), and GSPT2 (21%). The results of gene expression level analysis suggest the role of promoter methylation in downregulation of six out of nine genes examined. We did not find correlation between gene methylation and age, gender, tumor grade or stage. Importantly, in stage IV CRC methylation of GPR101 correlated with longer time to progression (P = 0.0042; HR = 2.5468; 95% CI 1.5391-10.0708).

Wu JC, Sun BS, Ren N, et al.
Genomic aberrations in hepatocellular carcinoma related to osteopontin expression detected by array-CGH.
J Cancer Res Clin Oncol. 2010; 136(4):595-601 [PubMed] Related Publications
PURPOSE: We have demonstrated that overexpression of osteopontin (OPN) could contribute to metastasis in hepatocellular carcinoma (HCC), and that OPN-positive cancer cells are often localized in the periphery of cancer nodules adjacent to stromal cells. This study was to identify the difference of intratumor genomic aberrations between OPN-positive and OPN-negative HCC cells.
METHODS: Immunohistochemical staining for OPN was performed in both archival and fresh HCC tumor tissues. Seven cases of OPN-positive HCC were chosen for laser capture microdissection. The OPN-positive and OPN-negative cancer cells were captured separately from serial frozen sections. Genomic DNA was extracted and quantified. Microarray-based comparative genomic hybridization (array-CGH) was used to achieve high-resolution analysis of whole-genome-wide aberrations.
RESULTS: The OPN expression level in HCC tissues was significantly associated with vascular or bile duct invasion (P = 0.003), Edmondson's grade (P = 0.047), and intrahepatic spreading (P = 0.011). When compared with the OPN-negative cancer cells, much more amplifications of chromosomal regions, including 4q13.1-q13.3, 4q21.23-q22.1, and 13q32.1-q32.3, were found in OPN-positive HCC cells. Some candidate tumor-related genes, such as SMR3B, MUC7, EPHA5, SPP1, and CLDN10 were detected with over 1.5-fold amplification.
CONCLUSIONS: There is a significant intratumor genomic heterogeneity between the OPN-positive and negative HCC cells, and OPN-positive HCC cells play a more important role in the development of HCC malignancy than their OPN-negative counterparts.

Fu DY, Wang ZM, Wang BL, et al.
Frequent epigenetic inactivation of the receptor tyrosine kinase EphA5 by promoter methylation in human breast cancer.
Hum Pathol. 2010; 41(1):48-58 [PubMed] Related Publications
EphA5 is a member of the Eph receptor tyrosine kinase family, which plays a critical role in the regulation of carcinogenesis. Our previous DNA methylation microarray results suggested that the CpG islands in the EphA5 promoter exhibited higher methylation levels in breast cancer tissues. In this study, we further analyzed EphA5 gene expression profiles, methylation status, and clinical implications in breast cancer. We found that the level of EphA5 mRNA was dramatically decreased in 5 different breast cancer cell lines. After treating the cell lines with 5-aza-2'-deoxycytidine (5-aza-dC, a demethylation agent), the levels of EphA5 mRNA and protein were significantly increased. Bisulfite sequencing and methylation-specific polymerase chain reaction detection showed that decreased expression of EphA5 was associated with its methylation status. We also found a significant correlation (P = .017) between the reduction of EphA5 mRNA levels and aberrant methylation of EphA5 in 31 paired tissue samples. In clinical samples, EphA5 methylation was detected in 64.1% (75/117) of breast tumors and 28.2% (33/117) of paired normal tissues (P < .001), which was associated with higher tumor grade (P = .024), lymph node metastasis (P = .004), and progesterone receptor-negative status (P = .008). Our data indicate that EphA5 might be a potential target for epigenetic silencing in primary breast cancer and a valuable molecular marker for breast cancer carcinogenesis and progression.

Almog N, Ma L, Raychowdhury R, et al.
Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype.
Cancer Res. 2009; 69(3):836-44 [PubMed] Related Publications
Tumor dormancy has important implications for early detection and treatment of cancer. Lack of experimental models and limited clinical accessibility constitute major obstacles to the molecular characterization of dormant tumors. We have developed models in which human tumors remain dormant for a prolonged period of time (>120 days) until they switch to rapid growth and become strongly angiogenic. These angiogenic tumors retain their ability to grow fast once injected in new mice. We hypothesized that dormant tumors undergo a stable genetic reprogramming during their switch to the fast-growing phenotype. Genome-wide transcriptional analysis was done to dissect the molecular mechanisms underlying the switch of dormant breast carcinoma, glioblastoma, osteosarcoma, and liposarcoma tumors. A consensus expression signature distinguishing all four dormant versus switched fast-growing tumors was generated. In alignment with our phenotypic observation, the angiogenesis process was the most significantly affected functional gene category. The switch of dormant tumors was associated with down-regulation of angiogenesis inhibitor thrombospondin and decreased sensitivity of angiogenic tumors to angiostatin. The conversion of dormant tumors to exponentially growing tumors was also correlated with regulation and activation of pathways not hitherto linked to tumor dormancy process, such as endothelial cell-specific molecule-1, 5'-ecto-nucleotidase, tissue inhibitor of metalloproteinase-3, epidermal growth factor receptor, insulin-like growth factor receptor, and phosphatidylinositol 3-kinase signaling. Further, novel dormancy-specific biomarkers such as H2BK and Eph receptor A5 (EphA5) were discovered. EphA5 plasma levels in mice and mRNA levels in tumor specimens of glioma patients correlated with diseases stage. These data will be instrumental in identifying novel early cancer biomarkers and could provide a rationale for development of dormancy-promoting tumor therapy strategies.

Sun B, Wu J, Zhang T, Wang C
High-resolution analysis of genomic profiles of hepatocellular carcinoma cells with differential osteopontin expression.
Cancer Biol Ther. 2008; 7(3):387-91 [PubMed] Related Publications
Overexpression of osteopontin (OPN) could contribute to tumorigenesis and metastasis in hepatocellular carcinoma (HCC). Previous studies have shown that OPN-positive cancer cells are often localized in the periphery of cancer nodules adjacent to stromal cells. To identify the difference in intratumor genomic aberration pattern between OPN-positive and OPN-negative HCC cells, we adopted microarray-based comparative genomic hybridization (array-CGH) to achieve high-resolution analysis of genome-wide aberrations. Our present study indicates that, compared to OPN-negative cancer cells, OPN-positive cancer cells show much more amplification of chromosomal regions, including 4q13.1-q13.3, 4q21.23-q22.1 and 13q32.1-q32.3. Some candidate tumor related genes, such as SMR3B, MUC7, EPHA5, SPP1 and CLDN10, were detected with over 1.5-fold amplification. Together, the intratumor genomic heterogeneity may suggest that OPN-positive cancer cells play a more important role in the development of HCC malignancy than their OPN-negative counterparts.

Miescher GC, Taylor V, Olivieri G, et al.
Extensive splice variation and localization of the EHK-1 receptor tyrosine kinase in adult human brain and glial tumors.
Brain Res Mol Brain Res. 1997; 46(1-2):17-24 [PubMed] Related Publications
EHK-1 is a neuronal ELK-related receptor tyrosine kinase which interacts with multiple, membrane-anchored ligands. Recent experiments have suggested a role for some of these ligands in the formation of neuronal pathways. Here, we report the isolation of human EHK-1 cDNAs and the localization of the human EHK-1 gene to chromosome 4q12. Six EHK-1 mRNA splice variants encoding cell-surface receptors with catalytic domains were identified in adult human brain where a 120-kDa EHK-1 protein predominates. Immunohistochemistry for EHK-1 reveals a dendritic staining pattern in cortical neurons and cerebellar Purkinje cells and a marked accumulation of EHK-1 in the somas of pyramidal neurons within the cortex and hippocampus. Interestingly, we have identified lineage aberrant expression of EHK-1 in a number of human gliomas. In addition to functions during development, EHK-1 may be involved in the maintenance of the adult nervous system and contribute to glioma development.

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Cite this page: Cotterill SJ. EPHA5, Cancer Genetics Web: http://www.cancer-genetics.org/EPHA5.htm Accessed:

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