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dc.contributor.authorMorris, M R
dc.contributor.authorGentle, D
dc.contributor.authorAbdulrahman, M
dc.contributor.authorClarke, Noel W
dc.contributor.authorBrown, Michael D
dc.contributor.authorKishida, Takeshi
dc.contributor.authorYao, M
dc.contributor.authorTeh, B T
dc.contributor.authorLatif, Farida
dc.contributor.authorMaher, Eamonn R
dc.date.accessioned2009-04-24T08:55:11Z
dc.date.available2009-04-24T08:55:11Z
dc.date.issued2008-01-29
dc.identifier.citationFunctional epigenomics approach to identify methylated candidate tumour suppressor genes in renal cell carcinoma. 2008, 98 (2):496-501 Br. J. Canceren
dc.identifier.issn0007-0920
dc.identifier.pmid18195710
dc.identifier.doi10.1038/sj.bjc.6604180
dc.identifier.urihttp://hdl.handle.net/10541/66153
dc.description.abstractPromoter region hypermethylation and transcriptional silencing is a frequent cause of tumour suppressor gene (TSG) inactivation in many human cancers. Previously, to identify candidate epigenetically inactivated TSGs in renal cell carcinoma (RCC), we monitored changes in gene expression in four RCC cell lines after treatment with the demethylating agent 5-azacytidine. This enabled us to identify HAI-2/SPINT2 as a novel epigenetically inactivated candidate RCC TSG. To identify further candidate TSGs, we undertook bioinformatic and molecular genetic evaluation of a further 60 genes differentially expressed after demethylation. In addition to HAI-2/SPINT2, four genes (PLAU, CDH1, IGFB3 and MT1G) had previously been shown to undergo promoter methylation in RCC. After bioinformatic prioritisation, expression and/or methylation analysis of RCC cell lines+/-primary tumours was performed for 34 genes. KRT19 and CXCL16 were methylated in RCC cell lines and primary RCC; however, 22 genes were differentially expressed after demethylation but did not show primary tumour-specific methylation (methylated in normal tissue (n=1); methylated only in RCC cell lines (n=9) and not methylated in RCC cell lines (n=12)). Re-expression of CXCL16 reduced growth of an RCC cell line in vitro. In a summary, a functional epigenomic analysis of four RCC cell lines using microarrays representing 11 000 human genes yielded both known and novel candidate TSGs epigenetically inactivated in RCC, suggesting that this is valid strategy for the identification of novel TSGs and biomarkers.
dc.language.isoenen
dc.subjectKidney Canceren
dc.subjectCell Line, Tumour
dc.subjectCancer Genes
dc.subjectGenes, Tumour Suppressor
dc.subjectCancer Stem Cells
dc.subject.meshCarcinoma, Renal Cell
dc.subject.meshCell Line, Tumor
dc.subject.meshChemokines, CXC
dc.subject.meshDNA Methylation
dc.subject.meshEpigenesis, Genetic
dc.subject.meshGene Expression Regulation, Neoplastic
dc.subject.meshGenes, Neoplasm
dc.subject.meshGenes, Tumor Suppressor
dc.subject.meshGenomics
dc.subject.meshHumans
dc.subject.meshKidney Neoplasms
dc.subject.meshNeoplastic Stem Cells
dc.subject.meshPromoter Regions, Genetic
dc.subject.meshReceptors, Scavenger
dc.subject.meshTransfection
dc.titleFunctional epigenomics approach to identify methylated candidate tumour suppressor genes in renal cell carcinoma.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK Renal Molecular Oncology Group, University of Birmingham, Birmingham B15 2TT, UK.en
dc.identifier.journalBritish Journal of Canceren
html.description.abstractPromoter region hypermethylation and transcriptional silencing is a frequent cause of tumour suppressor gene (TSG) inactivation in many human cancers. Previously, to identify candidate epigenetically inactivated TSGs in renal cell carcinoma (RCC), we monitored changes in gene expression in four RCC cell lines after treatment with the demethylating agent 5-azacytidine. This enabled us to identify HAI-2/SPINT2 as a novel epigenetically inactivated candidate RCC TSG. To identify further candidate TSGs, we undertook bioinformatic and molecular genetic evaluation of a further 60 genes differentially expressed after demethylation. In addition to HAI-2/SPINT2, four genes (PLAU, CDH1, IGFB3 and MT1G) had previously been shown to undergo promoter methylation in RCC. After bioinformatic prioritisation, expression and/or methylation analysis of RCC cell lines+/-primary tumours was performed for 34 genes. KRT19 and CXCL16 were methylated in RCC cell lines and primary RCC; however, 22 genes were differentially expressed after demethylation but did not show primary tumour-specific methylation (methylated in normal tissue (n=1); methylated only in RCC cell lines (n=9) and not methylated in RCC cell lines (n=12)). Re-expression of CXCL16 reduced growth of an RCC cell line in vitro. In a summary, a functional epigenomic analysis of four RCC cell lines using microarrays representing 11 000 human genes yielded both known and novel candidate TSGs epigenetically inactivated in RCC, suggesting that this is valid strategy for the identification of novel TSGs and biomarkers.


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