title: Genome-wide CpG island methylation analysis implicates novel genes in the pathogenesis of renal cell carcinoma.
abstract: In order to identify novel candidate tumor suppressor genes (TSGs) implicated in renal cell carcinoma (RCC), we performed genome-wide methylation profiling of RCC using the HumanMethylation27 BeadChips to assess methylation at > 14,000 genes. Two hundred and twenty hypermethylated probes representing 205 loci/genes were identified in genomic CpG islands. A subset of TSGs investigated in detail exhibited frequent tumor methylation, promoter methylation associated transcriptional silencing and reactivation after demethylation in RCC cell lines and down-regulation of expression in tumor tissue (e.g., SLC34A2 specifically methylated in 63% of RCC, OVOL1 in 40%, DLEC1 in 20%, TMPRSS2 in 26%, SST in 31% and BMP4 in 35%). As OVOL1, a putative regulator of c-Myc transcription, and SST (somatostatin) had not previously been linked to cancer and RCC, respectively, we (1) investigated their potential relevance to tumor growth by RNAi knockdown and found significantly increased anchorage-independent growth and (2) demonstrated that OVOL1 knockdown increased c-Myc mRNA levels.
authors.affiliation: Centre for Rare Diseases and Personalized Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ricketts
authors.forename: Mark R
authors.initials: MR
authors.lastname: Morris
authors.forename: Dean
authors.initials: D
authors.lastname: Gentle
authors.forename: Michael
authors.initials: M
authors.lastname: Brown
authors.forename: Naomi
authors.initials: N
authors.lastname: Wake
authors.forename: Emma R
authors.initials: ER
authors.lastname: Woodward
authors.forename: Noel
authors.initials: N
authors.lastname: Clarke
authors.forename: Farida
authors.initials: F
authors.lastname: Latif
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D005796:Genes / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology*; D017421:Sequence Analysis; D014407:Tumor Cells, Cultured