Deep sequencing reveals distinct patterns of DNA methylation in prostate cancer
- Jung H. Kim1,11,
- Saravana M. Dhanasekaran1,2,11,
- John R. Prensner1,
- Xuhong Cao1,
- Daniel Robinson1,
- Shanker Kalyana-Sundaram1,3,
- Christina Huang1,
- Sunita Shankar1,
- Xiaojun Jing1,
- Matthew Iyer1,
- Ming Hu4,12,
- Lee Sam1,2,
- Catherine Grasso1,
- Christopher A. Maher1,2,5,
- Nallasivam Palanisamy1,
- Rohit Mehra1,
- Hal D. Kominsky1,
- Javed Siddiqui1,
- Jindan Yu6,
- Zhaohui S. Qin7 and
- Arul M. Chinnaiyan1,2,5,8,9,10,13
- 1Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;
- 2Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;
- 3Department of Environmental Biotechnology, Bharathidasan University, Tiruchirappalli 620 024, India;
- 4Department of Biostatistics, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;
- 5Center for Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;
- 6Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA;
- 7Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, USA;
- 8Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;
- 9Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;
- 10Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
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↵11 These authors contributed equally to this work.
Abstract
Beginning with precursor lesions, aberrant DNA methylation marks the entire spectrum of prostate cancer progression. We mapped the global DNA methylation patterns in select prostate tissues and cell lines using MethylPlex–next-generation sequencing (M-NGS). Hidden Markov model–based next-generation sequence analysis identified ∼68,000 methylated regions per sample. While global CpG island (CGI) methylation was not differential between benign adjacent and cancer samples, overall promoter CGI methylation significantly increased from ∼12.6% in benign samples to 19.3% and 21.8% in localized and metastatic cancer tissues, respectively (P-value < 2 × 10−16). We found distinct patterns of promoter methylation around transcription start sites, where methylation occurred not only on the CGIs, but also on flanking regions and CGI sparse promoters. Among the 6691 methylated promoters in prostate tissues, 2481 differentially methylated regions (DMRs) are cancer-specific, including numerous novel DMRs. A novel cancer-specific DMR in the WFDC2 promoter showed frequent methylation in cancer (17/22 tissues, 6/6 cell lines), but not in the benign tissues (0/10) and normal PrEC cells. Integration of LNCaP DNA methylation and H3K4me3 data suggested an epigenetic mechanism for alternate transcription start site utilization, and these modifications segregated into distinct regions when present on the same promoter. Finally, we observed differences in repeat element methylation, particularly LINE-1, between ERG gene fusion-positive and -negative cancers, and we confirmed this observation using pyrosequencing on a tissue panel. This comprehensive methylome map will further our understanding of epigenetic regulation in prostate cancer progression.
Footnotes
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↵13 Corresponding author.
E-mail arul{at}umich.edu.
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[Supplemental material is available for this article. The next-generation sequencing and microarray data from this study have been submitted to the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession nos. GSE29155 and GSE27619, respectively.]
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Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.119347.110.
- Received December 14, 2010.
- Accepted April 28, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press
