DNA Methylation Alterations Exhibit Intraindividual Stability and Interindividual Heterogeneity in Prostate Cancer Metastases
Science Translational Medicine • 23 Jan 2013 • Vol 5, Issue 169 • p. 169ra10 • DOI: 10.1126/scitranslmed.3005211
Surveying the DNA Methylation “Cityscape” of Prostate Cancer
Alterations in DNA methylation are a hallmark of human cancers, including prostate cancer. Understanding which of these alterations “drive” cancer initiation, progression, and metastasis, and which of these are merely “passengers” not involved in the chain of causation, is a major translational challenge. To tackle this challenge in the context of metastatic prostate cancer, Aryee et al. carried out genome-scale analyses of DNA methylation alterations in multiple metastases from each of 13 men who had died of metastatic prostate cancer. To visualize both the frequency of each methylation alteration in the metastases and the consistency with which each alteration was maintained across all metastases from an individual, the authors created DNA methylation “cityscape” plots. These analyses revealed that each individual developed a unique DNA methylation signature that was largely maintained across all metastases within that individual. Additionally, a set of DNA “hypermethylation” alterations, defined as regions that were normally unmethylated but acquired cancer-specific DNA methylation, were enriched for prostate cancer “drivers.” Such DNA hypermethylation alterations are attractive potential targets for development of longitudinal markers and therapeutic strategies for prostate cancer management.
Abstract
Human cancers almost ubiquitously harbor epigenetic alterations. Although such alterations in epigenetic marks, including DNA methylation, are potentially heritable, they can also be dynamically altered. Given this potential for plasticity, the degree to which epigenetic changes can be subject to selection and act as drivers of neoplasia has been questioned. We carried out genome-scale analyses of DNA methylation alterations in lethal metastatic prostate cancer and created DNA methylation “cityscape” plots to visualize these complex data. We show that somatic DNA methylation alterations, despite showing marked interindividual heterogeneity among men with lethal metastatic prostate cancer, were maintained across all metastases within the same individual. The overall extent of maintenance in DNA methylation changes was comparable to that of genetic copy number alterations. Regions that were frequently hypermethylated across individuals were markedly enriched for cancer- and development/differentiation-related genes. Additionally, regions exhibiting high consistency of hypermethylation across metastases within individuals, even if variably hypermethylated across individuals, showed enrichment for cancer-related genes. Whereas some regions showed intraindividual metastatic tumor heterogeneity in promoter methylation, such methylation alterations were generally not correlated with gene expression. This was despite a general tendency for promoter methylation patterns to be strongly correlated with gene expression, particularly at regions that were variably methylated across individuals. These findings suggest that DNA methylation alterations have the potential for producing selectable driver events in carcinogenesis and disease progression and highlight the possibility of targeting such epigenome alterations for development of longitudinal markers and therapeutic strategies.
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Supplementary Material
Summary
Materials and Methods
Fig. S1. Filtering procedure used to select MBD-SNP probes.
Fig. S2. ASM and loss of ASM at the IGF2/H19 locus.
Fig. S3. Number of subjects affected by gains or losses of ASM falling within various genome annotations.
Fig. S4. Number of regions showing DNA methylation alterations stratified by number of affected subjects.
Fig. S5. Distribution of number of subjects showing alteration of a given region, stratified by genome annotation.
Fig. S6. Gene set enrichment analysis of hyper- and hypomethylated loci.
Fig. S7. Number of DNA methylation alterations in each subject.
Fig. S8. Distribution of number of probes within various genome annotations showing DNA methylation alterations in each subject.
Fig. S9. Distribution of CpG content of regions showing DNA methylation alterations.
Fig. S10. Copy number, TM, and ASM R2 distributions using the top 5% most variable probes in each category.
Fig. S11. Methylation R2 for the 44 MBD-SNP probes whose somatic hypermethylation status was verified in an independent data set from Kobayashi et al. (58).
Fig. S12. DNA methylation hierarchical clustering showing high within-subject similarity and between-subject heterogeneity of metastases.
Fig. S13. Multidimensional scaling plot of DNA methylation profiles of eight prostate tumors (red) from five individuals and four benign prostate specimens (green) analyzed on the Illumina HumanMethylation 450k microarray.
Fig. S14. Distribution of R2 for hyper- and hypomethylation alterations stratified by CpG density.
Fig. S15. Median gene expression by promoter methylation level.
Fig. S16. Representative genes, including those from development/differentiation gene sets, showing correlation between hypermethylation and loss of expression.
Fig. S17. Promoter DNA methylation R2 representing the degree of within-subject stability of methylation across anatomically distinct tumors.
Fig. S18. P values for association between gene expression and promoter DNA methylation in 18 prostate cancer tumor samples from five patients.
Fig. S19. Regions of DNA hypermethylation showing recurrent clonal evolution in multiple subjects.
Fig. S20. Regions of DNA hypomethylation showing recurrent clonal evolution in multiple subjects.
Fig. S21. Cityscape of gains and losses of ASM in lethal metastatic prostate cancer.
Fig. S22. Examples of genes in the hypermethylation cityscape (Fig. 5A).
Fig. S23. NCI cancer gene set enrichment for structures in the hypermethylation cityscape.
Fig. S24. Mixture model fit to the TM methylation score distribution.
Table S1. Number of probes/regions within specific genomic annotations.
Table S2. Summary of ASM at all interrogatable loci.
Table S3. Summary of DNA hypermethylation at all interrogatable loci.
Table S4. Analysis of differential expression between metastases and organ donor normal prostate tissues.
Table S5. Sample information.
Table S6. Subject demographics.
Resources
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Published In
Science Translational Medicine
Volume 5 | Issue 169
January 2013
January 2013
Copyright
Copyright © 2013, American Association for the Advancement of Science.
Submission history
Received: 23 October 2012
Accepted: 7 January 2013
Acknowledgments
We thank the family members and friends of the autopsy study participants and organ donor subjects, the Grove Foundation, and John and Kathe Dyson, who provided support to the PELICAN autopsy study. Funding: This work was supported by funding from the Department of Defense Prostate Cancer Research Program (PC073533/W81XH-08-1-0049), NIH (CA58236, CA070196, CA113374, CA135008, and GM083084), the Prostate Cancer Foundation Creativity and Challenge awards, the Patrick C. Walsh Prostate Cancer Research Fund/Dr. and Mrs. Peter S. Bing Scholarship (to S.Y.), the V Foundation for Cancer Research Martin D. Abeloff V Scholar Award (to S.Y.), the German Research Foundation Research Fellowship (to P.N.), the Finnish Academy of Sciences Finnish Distinguished Professor Award (to G.S.B.), the Commonwealth Foundation for Cancer Research, and Mr. David H. Koch and The Irving A. Hansen Memorial Foundation. We also acknowledge the support from the CapCURE Foundation (to W.B.I. and G.S.B.), which made the initiation of the PELICAN prostate cancer autopsy study possible. Author contributions: S.Y., G.S.B., R.H.G., J.L., W.G.N., J.X., and W.B.I. conceptualized the study. G.S.B. directed the PELICAN autopsy study of lethal prostate cancer from which prostate cancer tissue metastasis tissues were obtained. W.B.I. assisted in collection of autopsy study tissues. R.H.G. directed collection of normal human tissue specimens from organ donors. S.Y., W.L., M.C.H., P.N., J.L., and D.E. performed the experiments. M.J.A., S.Y., M.G., J.C.E., and R.A.I. designed computational methods and performed data analysis. M.J.A. and S.Y. wrote the manuscript. Competing interests: S.Y., M.C.H., D.E., W.G.N., W.B.I., and Johns Hopkins University (JHU) have provisional and/or fully executed patents relating to DNA methylation biomarkers in prostate cancer (U.S. Patent Number 5,552,277, “Genetic diagnosis of prostate cancer”; patent pending, “Epigenetic tests for prostate cancer”; patent pending, “DNA methylation biomarkers for prostate cancer”). S.Y. and W.G.N., along with JHU, hold a patent (U.S. Patent Number 7,906,288, “COMPARE-MS: A novel technique for rapid, sensitive, and specific detection of DNA methylation”) for the MBD2-MBD polypeptide for detection of methylated DNA. This reagent has been made available to the research community via a nonexclusive license with Clontech Inc., which provides royalties to JHU, S.Y., and W.G.N from sales of kits containing this reagent. The authors are pursuing intellectual property protection for the new prostate cancer biomarkers described here. Data and materials availability: Raw and normalized data are available from the GEO with accession number GSE38242.
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