Hypomethylation and hypermethylation of DNA in Wilms tumors

Abstract

We quantitatively analysed hypermethylation at CpG islands in the 5' ends of 12 genes and one non-CpG island 5' region (MTHFR) in 31 Wilms tumors. We also determined their global genomic 5-methylcytosine content. Compared with various normal postnatal tissues, *40 -90% of these pediatric kidney cancers were hypermethylated in four of the genes, MCJ, RASSF1A, TNFRSF12 and CALCA as determined by a quantitative bisulfite-based assay (MethyLight). Interestingly, the non-CpG island 5' region of MTHFR was less methylated in most tumors relative to the normal tissues. By chromatographic analysis of DNA digested to deoxynucleosides, about 60% of the Wilms tumors were found to be deficient in their overall levels of DNA methylation. We also analysed expression of the three known functional DNA methyltransferase genes. No relationship was observed between global genomic 5-methylcytosine levels and relative amounts of RNA for DNA methyltransferases DNMT1, DNMT3A, and DNMT3B. Importantly, no association was seen between CpG island hypermethylation and global DNA hypomethylation in these cancers. Therefore, the overall genomic hypomethylation frequently observed in cancers is probably not just a response or a prelude to hypermethylation elsewhere in the genome. This suggests that the DNA hypomethylation contributes independently to oncogenesis or tumor progression.

Epigenetic inactivation ofMCJ (DNAJD1) in malignant paediatric brain tumours

“…We demonstrate hypermethylation of the MCJ intronic CpG island 16,17 26 and >50% of ovarian cancers; 16,17 however, MCJ hypermethylation has not been investigated in other tumour types. Our observations of MCJ hypermethylation in medulloblastomas, stPNETs and ependymomas suggest that MCJ inactivation plays a role in the development of a range of CNS tumour types, and this role now requires further investigation and clarification.…”

“…Tumourspecific methylation of MCJ has also been reported in Wilms' tumours; 26 however, this is in contrast to ovarian cancers, where MCJ methylation is also a feature of the normal ovarian epithelium. 17 Strathdee et al 17 reported that the MCJ CpG island is methylated and the gene is not expressed in cells of epithelial origin but is unmethylated and expressed in cells of lymphocytic or fibroblast origin.…”

DNA hypomethylation is prevalent even in low-grade breast cancers

“…The overall m 5 C content of the DNA was determined by high performance liquid chromatography (HPLC) 24 on heat-denatured DNA digested with nuclease P1 and bacterial alkaline phosphatase for 2 h at 37˚C each.…”

“…Furthermore, we found, that a much higher percentage of Wilms tumors exhibited hypomethylation of Sat2 than pericentromeric rearrangements in Sat2 DNA-rich chromosomes as determined by karyotype analysis. 14 Because the high frequencies of cancer-linked satellite DNA hypomethylation are not positively associated with cancer-linked CpG island hypermethylation of tumor suppressor genes 8,24 (Laird P, Dubeau L, Ehrlich M, unpublished data), this hypomethylation is not likely to be just a byproduct of or preliminary to CpG island hypermethylation. These findings suggest that there are other ways by which cancer-linked satellite DNA hypomethylation contributes to oncogenesis besides favoring karyotypic instability, e.g., possibly by influencing gene expression in trans.…”

Foetal haemoglobin-blood cells (F-cells) as a feature of embryonic tumours (blastomas)

“…Hence, DNhpom agents might promote neoplasia in prospective tumour cells simultaneously with reactivation of HbF gene expression in erythrocytes precursors, residing inside the tumour tissues or in haematopoietic tissues of the same organism. This hypothesis is not impaired by the evidence for inactivation of tumour suppressing genes by DNA hypermethylation, since hypermethylation is specific for unique genomic sites while at the same time global DNA is hypomethylated (Ehrlich et al, 2002;Brothman et al, 2005;Ehrlich, 2005). By that ambiguity, the use of DNA demethylating agents as therapeutic anticancer regiment might contribute to carcinogenesis (Ehrlich, 2005).…”