The DNA methylation landscape of advanced prostate cancer

Shuang G. Zhao, William S. Chen, Haolong Li, Adam Foye, Meng Zhang, Martin Sjöström, Rahul Aggarwal, Denise Playdle, Arnold Liao, Joshi J. Alumkal, Rajdeep Das, Jonathan Chou, Junjie T. Hua, Travis J. Barnard, Adina M. Bailey, Eric D. Chow, Marc D. Perry, Ha X. Dang, Rendong Yang, Ruhollah Moussavi-BaygiLi Zhang, Mohammed Alshalalfa, S. Laura Chang, Kathleen E. Houlahan, Yu Jia Shiah, Tomasz M. Beer, George Thomas, Kim N. Chi, Martin Gleave, Amina Zoubeidi, Robert E. Reiter, Matthew B. Rettig, Owen Witte, M. Yvonne Kim, Lawrence Fong, Daniel E. Spratt, Todd M. Morgan, Rohit Bose, Franklin W. Huang, Hui Li, Lisa Chesner, Tanushree Shenoy, Hani Goodarzi, Irfan A. Asangani, Shahneen Sandhu, Joshua M. Lang, Nupam P. Mahajan, Primo N. Lara, Christopher P. Evans, Phillip Febbo, Serafim Batzoglou, Karen E. Knudsen, Housheng H. He, Jiaoti Huang, Wilbert Zwart, Joseph F. Costello, Jianhua Luo, Scott A. Tomlins, Alexander W. Wyatt, Scott M. Dehm, Alan Ashworth, Luke A. Gilbert, Paul C. Boutros, Kyle Farh, Arul M. Chinnaiyan, Christopher A. Maher, Eric J. Small, David A. Quigley, Felix Y. Feng

Research output: Contribution to journalArticlepeer-review

120 Scopus citations


Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome approaches. Notably, we observed that 22% of tumors exhibited a novel epigenomic subtype associated with hypermethylation and somatic mutations in TET2, DNMT3B, IDH1 and BRAF. We also identified intergenic regions where methylation is associated with RNA expression of the oncogenic driver genes AR, MYC and ERG. Finally, we showed that differential methylation during progression preferentially occurs at somatic mutational hotspots and putative regulatory regions. This study is a large integrated study of whole-genome, whole-methylome and whole-transcriptome sequencing in metastatic cancer that provides a comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer.

Original languageEnglish (US)
Pages (from-to)778-789
Number of pages12
JournalNature Genetics
Issue number8
StatePublished - Aug 1 2020

Bibliographical note

Funding Information:
We thank the patients who selflessly contributed samples to this study and without whom this research would not have been possible. We would also like to acknowledge the assistance of Steven Kronenberg and Barbara Panning. This research was supported by a Stand Up To Cancer-Prostate Cancer Foundation Prostate Cancer Dream Team Award (SU2C-AACR-DT0812 to E.J.S.) and by the Movember Foundation. Stand Up To Cancer is a division of the Entertainment Industry Foundation. This research grant was administered by the American Association for Cancer Research, the scientific partner of SU2C. S.G.Z., D.A.Q., Hui Li, R.A., J.T.H., R.B. and R.Y. were funded by Prostate Cancer Foundation Young Investigator Awards. F.Y.F. was funded by Prostate Cancer Foundation Challenge Awards. Additional funding was provided by a UCSF Benioff Initiative for Prostate Cancer Research award. F.Y.F. and A.A. were supported by National Institutes of Health (NIH)/National Cancer Institute (NCI) 1R01CA230516-01. F.Y.F. and N.M. were supported by NIH/NCI 1R01CA227025 and Prostate Cancer Foundation (PCF) 17CHAL06. F.Y.F. and A.M.C. were supported by NIH P50CA186786. A.M.C. is supported by NIH R35CA231996 and U01CA214170. D.A.Q. was funded by a BRCA Foundation Young Investigator Award. M.S. was supported by the Swedish Research Council (Vetenskapsrådet) with grant number 2018–00382 and the Swedish Society of Medicine (Svenska Läkaresällskapet). L.A.G. was supported by K99/R00 CA204602 and DP2 CA239597, as well as the Goldberg-Benioff Endowed Professorship in Prostate Cancer Translational Biology. P.C.B. was supported by the NIH/NCI under award number P30CA016042 and by an operating grant from the National Cancer Institute Early Detection Research Network (1U01CA214194-01).

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.


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