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.

Epigenetic modification induced by hepatitis B virus X protein via interaction with de novo DNA methyltransferase DNMT3A

“…Altered global DNA methylation patterns, specifically hypomethylation, have been reported for many cancers [27][28][29][30][31] including HCC [32]. However, whether HBV or HBx was involved in epigenetic modification during HCC carcinogenesis remains unclear.…”

The CAP Superfamily: Cysteine-Rich Secretory Proteins, Antigen 5, and Pathogenesis-Related 1 Proteins—Roles in Reproduction, Cancer, and Immune Defense

“…WT has a complex etiology and is associated with both genetic and epigenetic changes (262)(263)(264)(265)(266). Using a comparative analysis of differentially methylated regions in the genomes of normal fetal and WT kidney tissue, Chilukamarri et al (267) identified the GLIPR1 promoter as being a frequently hypomethylated locus in WT. Consistent with this, GLIPR1 mRNA and proteins were significantly up-regulated in the majority of WT tissues examined (267).…”

DNA Methylation and Nonsmall Cell Lung Cancer

“…Furthermore, CpG methylation density is very important due to a fact that low-density CpG methylation would merely repress a weak promoter, while high-density methylation is required for inhibition of a strong promoter (Bird, 1992). Global hypomethylation (Esteller and Herman, 2002) and regional promoter CGIs hypomethylation (Chilukamarri et al, 2007;Lin et al, 2007b;Kim et al, 2008) may activate proto-oncogenes, loss gene imprinting, and reactivate transposable elements. Nevertheless, hypermethylated CGIs may suppress the expression of genes that contribute to tumor suppression, chromatin condensation, and DNA repair (Baylin, 2005).…”