The 5-Hydroxymethylcytosine Landscape of Prostate Cancer.

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 whole-genome 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 cell-free 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.

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.

Cancer research. 2022 Oct 17 [Epub ahead of print]

Martin Sjöström, 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-Dror, Ashutosh Maheshwari, Sujun Chen, Sarah W S Ng, Wenbin Ye, Jessica Petricca, Michael Fraser, Lisa Chesner, Marc D Perry, Thaidy Moreno-Rodriguez, 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

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA., Department of Human Oncology, University of Wisconsin-Madison, Madison, WI., Bluestar Genomics Inc., San Diego, CA., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada., Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Division of Hematology and Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI., Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Knight Cancer Institute, Oregon Health and Science University, Portland, OR., Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA., Departments of Medicine, Hematology/Oncology and Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA., Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA., Department of Pathology, University of Pittsburgh, Pittsburgh, PA., Department of Translational Medicine, Medical Faculty, Lund University, Malmö, Sweden., Department of Medicine, University of Wisconsin-Madison, Madison, WI., Siteman Cancer Center, Washington University, St. Louis, MO., Division of Hematology Oncology, Department of Internal Medicine, University of California Davis, Sacramento, CA., Comprehensive Cancer Center, University of California Davis, Sacramento, CA., Department of Radiation Oncology, University of Maryland, College Park, Baltimore, MD., Urologic Oncology Program & Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA., Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL., Department of Pathology, Duke University, Durham, NC., Netherlands Cancer Institute, Oncode Institute, Amsterdam, the Netherlands.

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