Quantitative analysis of associations between DNA hypermethylation, hypomethylation, and DNMT RNA levels in ovarian tumors

• Published in: Oncogene Vol. 25; no. 18; pp. 2636 - 2645
• Main Authors: EHRLICH, M, WOODS, C. B, LAIRD, P. W, YU, M. C, DUBEAU, L, YANG, F, CAMPAN, M, WEISENBERGER, D. J, LONG, T. I, YOUN, B, FIALA, E. S
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 27-04-2006; Nature Publishing Group
• Subjects: Adenocarcinoma, Mucinous - genetics; Adenocarcinoma, Mucinous - pathology; Adolescent; Adult; Aged; Biological and medical sciences; Cancer; Carcinoma, Endometrioid - genetics; Carcinoma, Endometrioid - pathology; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cystadenoma, Serous - genetics; Cystadenoma, Serous - pathology; Deoxyribonucleic acid; DNA; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA Methylation; DNA methyltransferase; DNA, Neoplasm; DNMT1 protein; E-cadherin; Female; Female genital diseases; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation, Neoplastic; Genomes; Gynecology. Andrology. Obstetrics; Humans; ICF syndrome; Isoforms; Malignancy; Medical sciences; Methylenetetrahydrofolate reductase; Middle Aged; Molecular and cellular biology; Neoplasm Proteins - genetics; Oncology; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Ovaries; Quantitative analysis; Ribonucleic acid; RNA; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; Satellite DNA; Satellite RNA; Tumor Suppressor Proteins; Tumors; RNA; ovarian tumors; Enzyme; Transferases; DNA hypermethylation; DNA methyltransferases; Carcinogenesis; Female genital diseases; Ovarian diseases; Association; Methyltransferases; DNA; Methylation; DNA hypomethylation; Quantitative analysis; Ovarian tumor
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1209145

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.