Hypomethylation and hypermethylation of DNA in Wilms tumors.
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, approximately 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.
Ehrlich
Melanie
M
Tulane Cancer Center and Human Genetics Program, Tulane Medical School, New Orleans, Louisiana, LA 70112, USA. ehrlich@tulane.edu
Jiang
Guanchao
G
Fiala
Emerich
E
Dome
Jeffrey S
JS
Yu
Mimi C
MC
Long
Tiffany I
TI
Youn
Byungwoo
B
Sohn
Ock-Soon
OS
Widschwendter
Martin
M
Tomlinson
Gail E
GE
Chintagumpala
Murali
M
Champagne
Martin
M
Parham
David
D
Liang
Gangning
G
Malik
Karim
K
Laird
Peter W
PW
D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D016147:Genes, Tumor Suppressor; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D025521:Tumor Suppressor Proteins; D009396:Wilms Tumor / Q000235:genetics*; D000097584:DNA Methyltransferase 3B
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C411762:RASSF1 protein, human; C000619380:DNMT1 protein, human