The 5-Hydroxymethylcytosine Landscape of Prostate Cancer

Martin Sjostrom, Shuang G. Zhao, Samuel Levy, Meng Zhang, Yuhong Ning, Raunak Shrestha, Arian Lundberg, Cameron Herberts, Adam Foye, Rahul Aggarwal, Junjie T. Hua, Haolong Li, Anna Bergamaschi, Corinne Maurice-Dro, Ashutosh Maheshwari, Sujun Chen, Sarah W.S. Ng, Wenbin Ye, Jessica Petricca, Michael FraserLisa Chesner, Marc D. Perry, Thaidy Moreno-Rodrigue, William S. Chen, Joshi J. Alumkal, Jonathan Chou, Alicia K. Morgans, Tomasz M. Beer, George V. Thomas, Martin Gleave, Paul Lloyd, Tierney Phillips, Erin McCarthy, Michael C. Haffner, Amina Zoubeidi, Matti Annala, Robert E. Reiter, Matthew B. Rettig, Owen N. Witte, Lawrence Fong, Rohit Bose, Franklin W. Huang, Jianhua Luo, Anders Bjartell, Joshua M. Lang, Nupam P. Mahajan, Primo N. Lara, Christopher P. Evans, Phuoc T. Tran, Edwin M. Posadas, Chuan He, Xiao Long Cui, Jiaoti Huang, Wilbert Zwart, Luke A. Gilbert, Christopher A. Maher, Paul C. Boutros, Kim N. Chi, Alan Ashworth, Eric J. Small, Housheng H. He, Alexander W. Wyatt, David A. Quigley, Felix Y. Feng*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating wholegenome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cellfree DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease. Significance: In prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880.

Original languageEnglish (US)
Pages (from-to)3888-3902
Number of pages15
JournalCancer Research
Issue number21
StatePublished - Nov 1 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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