title: Hypomethylation and aberrant expression of the glioma pathogenesis-related 1 gene in Wilms tumors.
abstract: Wilms tumors (WTs) have a complex etiology, displaying genetic and epigenetic changes, including loss of imprinting (LOI) and tumor suppressor gene silencing. To identify new regions of epigenetic perturbation in WTs, we screened kidney and tumor DNA using CpG island (CGI) tags associated with cancer-specific DNA methylation changes. One such tag corresponded to a paralog of the glioma pathogenesis-related 1/related to testis-specific, vespid, and pathogenesis proteins 1 (GLIPR1/RTVP-1) gene, previously reported to be a tumor-suppressor gene silenced by hypermethylation in prostate cancer. Here we report methylation analysis of the GLIPR1/RTVP-1 gene in WTs and normal fetal and pediatric kidneys. Hypomethylation of the GLIPR1/RTVP-1 5'-region in WTs relative to normal tissue is observed in 21/24 (87.5%) of WTs analyzed. Quantitative analysis of GLIPR1/RTVP-1 expression in 24 WTs showed elevated transcript levels in 16/24 WTs (67%), with 12 WTs displaying in excess of 20-fold overexpression relative to fetal kidney (FK) control samples. Immunohistochemical analysis of FK and WT corroborates the RNA expression data and reveals high GLIPR1/RTVP-1 in WT blastemal cells together with variable levels in stromal and epithelial components. Hypomethylation is also evident in the WT precursor lesions and nephrogenic rests (NRs), supporting a role for GLIPR1/RTVP-1 deregulation early in Wilms tumorigenesis. Our data show that, in addition to gene dosage changes arising from LOI and hypermethylation-induced gene silencing, gene activation resulting from hypomethylation is also prevalent in WTs.
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Laxmi
authors.initials: L
authors.lastname: Chilukamarri
authors.forename: Anne L
authors.initials: AL
authors.lastname: Hancock
authors.forename: Sally
authors.initials: S
authors.lastname: Malik
authors.forename: Joanna
authors.initials: J
authors.lastname: Zabkiewicz
authors.forename: Jenny A
authors.initials: JA
authors.lastname: Baker
authors.forename: Alexander
authors.initials: A
authors.lastname: Greenhough
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Dallosso
authors.forename: Tim Hui-Ming
authors.initials: TH
authors.lastname: Huang
authors.forename: Brigitte
authors.initials: B
authors.lastname: Royer-Pokora
authors.forename: Keith W
authors.initials: KW
authors.lastname: Brown
authors.forename: Karim
authors.initials: K
authors.lastname: Malik
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001374:Azacitidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D001483:Base Sequence; D002648:Child; D019175:DNA Methylation; D000077209:Decitabine; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D015533:Transcriptional Activation; D009396:Wilms Tumor / Q000235:genetics*
chemical_list: C094538:GLIPR1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000077209:Decitabine; D001374:Azacitidine