DNA methylation changes in ovarian cancer are cumulative with disease progression and identify tumor stage

Persistent Link:
http://hdl.handle.net/10150/610037
Title:
DNA methylation changes in ovarian cancer are cumulative with disease progression and identify tumor stage
Author:
Watts, George; Futscher, Bernard; Holtan, Nicholas; DeGeest, Koen; Domann, Frederick; Rose, Stephen
Affiliation:
Department 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
Issue Date:
2008
Publisher:
BioMed Central
Citation:
BMC Medical Genomics 2008, 1:47 doi:10.1186/1755-8794-1-47
Journal:
BMC 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 Information:
This 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 repository@u.library.arizona.edu.
Abstract:
BACKGROUND: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.
EISSN:
1755-8794
DOI:
10.1186/1755-8794-1-47
Version:
Final published version
Additional Links:
http://www.biomedcentral.com/1755-8794/1/47

Full metadata record

DC FieldValue Language
dc.contributor.authorWatts, Georgeen
dc.contributor.authorFutscher, Bernarden
dc.contributor.authorHoltan, Nicholasen
dc.contributor.authorDeGeest, Koenen
dc.contributor.authorDomann, Fredericken
dc.contributor.authorRose, Stephenen
dc.date.accessioned2016-05-20T08:57:07Z-
dc.date.available2016-05-20T08:57:07Z-
dc.date.issued2008en
dc.identifier.citationBMC Medical Genomics 2008, 1:47 doi:10.1186/1755-8794-1-47en
dc.identifier.doi10.1186/1755-8794-1-47en
dc.identifier.urihttp://hdl.handle.net/10150/610037-
dc.description.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 progressionen
dc.description.abstract659 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.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://www.biomedcentral.com/1755-8794/1/47en
dc.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)en
dc.titleDNA methylation changes in ovarian cancer are cumulative with disease progression and identify tumor stageen
dc.typeArticleen
dc.identifier.eissn1755-8794en
dc.contributor.departmentDepartment of Medical Pharmacology, College of Medicine, University of Arizona, Tucson AZ 85724 USAen
dc.contributor.departmentDepartment of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson AZ 85724 USAen
dc.contributor.departmentArizona Cancer Center, University of Arizona, Tucson AZ 85724 USAen
dc.contributor.departmentDepartment of Obstetrics and Gynecology, Free Radical & Radiation Biology Program, University of Iowa, Iowa City IA 52242 USAen
dc.contributor.departmentDepartment of Radiation Oncology, Free Radical & Radiation Biology Program, University of Iowa, Iowa City IA 52242 USAen
dc.contributor.departmentDepartment of Obstetrics and Gynecology, University of Wisconsin, Madison WI, 53792, USAen
dc.identifier.journalBMC Medical Genomicsen
dc.description.collectioninformationThis 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 repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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