1. ¹Tulane Cancer Center, Department of Biochemistry, and Human Genetics Program, Tulane Medical School, New Orleans, LA, USA
2. ²University of Minnesota Cancer Center, Minneapolis, Minnesota, USA
3. ³Department of Pathology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, USA
4. ⁴Department of Biochemistry, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, USA
5. ⁵Department of Surgery and Molecular Biology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, USA
6. ⁶Department of Biochemical Pharmacology, American Health Foundation, Valhalla, NY, USA
7. ⁷New York University School of Medicine, Tuxedo, NY, USA

Correspondence: Dr M Ehrlich, Human Genetics Program SL31, Tulane Medical School, 1430 Tulane Ave., New Orleans, LA 70112, USA. E-mail: ehrlich@tulane.edu

Received 1 July 2005; Revised 25 August 2005; Accepted 25 August 2005; Published online 13 March 2006.

Abstract

How hypermethylation and hypomethylation of different parts of the genome in cancer are related to each other and to DNA methyltransferase (DNMT) gene expression is ill defined. We used ovarian epithelial tumors of different malignant potential to look for associations between 5'-gene region or promoter hypermethylation, satellite, or global DNA hypomethylation, and RNA levels for ten DNMT isoforms. In the quantitative MethyLight assay, six of the 55 examined gene loci (LTB4R, MTHFR, CDH13, PGR, CDH1, and IGSF4) were significantly hypermethylated relative to the degree of malignancy (after adjustment for multiple comparisons; P<0.001). Importantly, hypermethylation of these genes was associated with degree of malignancy independently of the association of satellite or global DNA hypomethylation with degree of malignancy. Cancer-related increases in methylation of only two studied genes, LTB4R and MTHFR, which were appreciably methylated even in control tissues, were associated with DNMT1 RNA levels. Cancer-linked satellite DNA hypomethylation was independent of RNA levels for all DNMT3B isoforms, despite the ICF syndrome-linked DNMT3B deficiency causing juxtacentromeric satellite DNA hypomethylation. Our results suggest that there is not a simple association of gene hypermethylation in cancer with altered DNMT RNA levels, and that this hypermethylation is neither the result nor the cause of satellite and global DNA hypomethylation.