This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yegnasubramanian, S. Articles by Nelson, W. G. Search for Related Content PubMed PubMed Citation Articles by Yegnasubramanian, S. Articles by Nelson, W. G.

DNA Hypomethylation Arises Later in Prostate Cancer Progression than CpG Island Hypermethylation and Contributes to Metastatic Tumor Heterogeneity

¹ Sidney Kimmel Comprehensive Cancer Center, ² Department of Radiation Oncology, ³ Department of Pathology, ⁴ Brady Urological Institute, ⁵ Department of Biostatistics, School of Public Health, Johns Hopkins University, Baltimore, Maryland; ⁶ Center for Statistical Sciences, Brown University, Providence, Rhode Island; and ⁷ Innsbruck Medical University, Innsbruck, Austria

Requests for reprints: Srinivasan Yegnasubramanian, 1650 Orleans Street, CRB1 Room 1M53, Baltimore, MD 21231. Phone: 410-502-3425; Fax: 410-502-9817; E-mail: syegnasu{at}jhmi.edu and William G. Nelson, 1650 Orleans Street, CRB1 Room 151, Baltimore, MD 21231. E-mail: bnelson{at}jhmi.edu.

Key Words: DNA methylation • hypomethylation • prostate cancer • metastasis • epigenetics • LINE1 • tumor heterogeneity • cancer testis antigens

Hypomethylation of CpG dinucleotides in genomic DNA was one of the first somatic epigenetic alterations discovered in human cancers. DNA hypomethylation is postulated to occur very early in almost all human cancers, perhaps facilitating genetic instability and cancer initiation and progression. We therefore examined the nature, extent, and timing of DNA hypomethylation changes in human prostate cancer. Contrary to the prevailing view that global DNA hypomethylation changes occur extremely early in all human cancers, we show that reductions in ^5meC content in the genome occur very late in prostate cancer progression, appearing at a significant extent only at the stage of metastatic disease. Furthermore, we found that, whereas some LINE1 promoter hypomethylation does occur in primary prostate cancers compared with normal tissues, this LINE1 hypomethylation is significantly more pronounced in metastatic prostate cancer. Next, we carried out a tiered gene expression microarray and bisulfite genomic sequencing–based approach to identify genes that are silenced by CpG island methylation in normal prostate cells but become overexpressed in prostate cancer cells as a result of CpG island hypomethylation. Through this analysis, we show that a class of cancer testis antigen genes undergoes CpG island hypomethylation and overexpression in primary prostate cancers, but more so in metastatic prostate cancers. Finally, we show that DNA hypomethylation patterns are quite heterogeneous across different metastatic sites within the same patients. These findings provide evidence that DNA hypomethylation changes occur later in prostate carcinogenesis than the CpG island hypermethylation changes and occur heterogeneously during prostate cancer progression and metastatic dissemination. [Cancer Res 2008;68(21):8954–67]

This article has been cited by other articles:

				J. Lin, J. Gilbert, M. A. Rudek, J. A. Zwiebel, S. Gore, A. Jiemjit, M. Zhao, S. D. Baker, R. F. Ambinder, J. G. Herman, et al. A Phase I Dose-Finding Study of 5-Azacytidine in Combination with Sodium Phenylbutyrate in Patients with Refractory Solid Tumors Clin. Cancer Res., October 1, 2009; 15(19): 6241 - 6249. [Abstract] [Full Text] [PDF]

				W. G. Nelson, A. M. De Marzo, and S. Yegnasubramanian Epigenetic Alterations in Human Prostate Cancers Endocrinology, September 1, 2009; 150(9): 3991 - 4002. [Abstract] [Full Text] [PDF]

				P. G. Febbo Epigenetic Events Highlight the Challenge of Validating Prognostic Biomarkers During the Clinical and Biologic Evolution of Prostate Cancer J. Clin. Oncol., July 1, 2009; 27(19): 3088 - 3090. [Full Text] [PDF]