DNA methylation changes in ovarian cancer are cumulative with disease progression and identify tumor stage
AffiliationDepartment of Medical Pharmacology, College of Medicine, University of Arizona, Tucson AZ 85724 USA
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson AZ 85724 USA
Arizona Cancer Center, University of Arizona, Tucson AZ 85724 USA
Department of Obstetrics and Gynecology, Free Radical & Radiation Biology Program, University of Iowa, Iowa City IA 52242 USA
Department of Radiation Oncology, Free Radical & Radiation Biology Program, University of Iowa, Iowa City IA 52242 USA
Department of Obstetrics and Gynecology, University of Wisconsin, Madison WI, 53792, USA
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CitationBMC Medical Genomics 2008, 1:47 doi:10.1186/1755-8794-1-47
JournalBMC Medical Genomics
Rights© 2008 Watts et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)
Collection InformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at firstname.lastname@example.org.
AbstractBACKGROUND:Hypermethylation of promoter CpG islands with associated loss of gene expression, and hypomethylation of CpG-rich repetitive elements that may destabilize the genome are common events in most, if not all, epithelial cancers.METHODS:The methylation of 6,502 CpG-rich sequences spanning the genome was analyzed in 137 ovarian samples (ten normal, 23 low malignant potential, 18 stage I, 16 stage II, 54 stage III, and 16 stage IV) ranging from normal tissue through to stage IV cancer using a sequence-validated human CpG island microarray. The microarray contained 5' promoter-associated CpG islands as well as CpG-rich satellite and Alu repetitive elements.RESULTS:Results showed a progressive de-evolution of normal CpG methylation patterns with disease progression
659 CpG islands showed significant loss or gain of methylation. Satellite and Alu sequences were primarily associated with loss of methylation, while promoter CpG islands composed the majority of sequences with gains in methylation. Since the majority of ovarian tumors are late stage when diagnosed, we tested whether DNA methylation profiles could differentiate between normal and low malignant potential (LMP) compared to stage III ovarian samples. We developed a class predictor consisting of three CpG-rich sequences that was 100% sensitive and 89% specific when used to predict an independent set of normal and LMP samples versus stage III samples. Bisulfite sequencing confirmed the NKX-2-3 promoter CpG island was hypermethylated with disease progression. In addition, 5-aza-2'-deoxycytidine treatment of the ES2 and OVCAR ovarian cancer cell lines re-expressed NKX-2-3. Finally, we merged our CpG methylation results with previously published ovarian expression microarray data and identified correlated expression changes.CONCLUSION:Our results show that changes in CpG methylation are cumulative with ovarian cancer progression in a sequence-type dependent manner, and that CpG island microarrays can rapidly discover novel genes affected by CpG methylation in clinical samples of ovarian cancer.
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