Hypomethylation and Aberrant Expression of the Glioma Pathogenesis-Related 1 Gene in Wilms Tumors

Wilms tumours (WTs) have a complex aetiology, displaying genetic and epigenetic changes, including loss of imprinting and tumour suppressor gene silencing. In order to identify new regions of epigenetic perturbation in WTs, we screened kidney and tumour DNAs using CpG island tags associated with cancer-specific DNA methylation changes. One such tag corresponded to a paralogue of the GLIPR1/RTVP-1 gene, previously reported to be a tumour suppressor gene silenced by hypermethylation in prostate cancer. Here we report methylation analysis of the GLIPR1/RTVP-1 gene in WTs and normal foetal and paediatric kidneys. Hypomethylation of the GLIPR1/RTVP-1 5'-region in WTs relative to normal tissue is observed in 21/24 (87.5%) of WTs analysed. 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 over-expression relative to foetal kidney control samples. Immunohistochemical analysis of foetal kidney and Wilms'tumour 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, nephrogenic rests, supporting a role for GLIPR1/RTVP-1 deregulation early in Wilms' tumorigenesis. Our data shows that, in addition to gene dosage changes arising from loss of imprinting and hypermethylation-induced gene silencing, gene activation resulting from hypomethylation is also prevalent in WTs.