The 5-Hydroxymethylcytosine Landscape of Prostate Cancer-Reference-Cited by-同舟云学术

The 5-Hydroxymethylcytosine Landscape of Prostate Cancer

Published:2022-10-17 Issue:21 Volume:82 Page:3888-3902
ISSN:0008-5472
Container-title:Cancer Research
language:en
Short-container-title:

Author:

Sjöström Martin¹²³^ORCID,Zhao Shuang G.⁴⁵,Levy Samuel⁶^ORCID,Zhang Meng¹²^ORCID,Ning Yuhong⁶,Shrestha Raunak¹²^ORCID,Lundberg Arian¹²^ORCID,Herberts Cameron⁷^ORCID,Foye Adam¹⁸^ORCID,Aggarwal Rahul¹⁸^ORCID,Hua Junjie T.¹²^ORCID,Li Haolong¹²,Bergamaschi Anna⁶^ORCID,Maurice-Dror Corinne⁷⁹^ORCID,Maheshwari Ashutosh¹²,Chen Sujun¹⁰¹¹,Ng Sarah W.S.⁷^ORCID,Ye Wenbin¹⁰¹¹¹²^ORCID,Petricca Jessica¹⁰¹¹,Fraser Michael¹¹¹³,Chesner Lisa¹²,Perry Marc D.¹²^ORCID,Moreno-Rodriguez Thaidy¹²^ORCID,Chen William S.¹²,Alumkal Joshi J.¹⁴^ORCID,Chou Jonathan¹⁸^ORCID,Morgans Alicia K.¹⁵,Beer Tomasz M.¹⁶^ORCID,Thomas George V.¹⁶¹⁷,Gleave Martin⁷,Lloyd Paul⁶^ORCID,Phillips Tierney⁶,McCarthy Erin⁶^ORCID,Haffner Michael C.¹⁸¹⁹^ORCID,Zoubeidi Amina⁷^ORCID,Annala Matti⁷²⁰,Reiter Robert E.²¹²²^ORCID,Rettig Matthew B.²¹²²²³^ORCID,Witte Owen N.²⁴^ORCID,Fong Lawrence¹⁸^ORCID,Bose Rohit¹⁸²⁵²⁶^ORCID,Huang Franklin W.¹⁸,Luo Jianhua²⁷^ORCID,Bjartell Anders²⁸²⁹,Lang Joshua M.³⁰^ORCID,Mahajan Nupam P.³¹^ORCID,Lara Primo N.³²³³,Evans Christopher P.³³³⁴^ORCID,Tran Phuoc T.³⁵^ORCID,Posadas Edwin M.³⁶^ORCID,He Chuan³⁷³⁸,Cui Xiao-Long³⁷³⁸,Huang Jiaoti³⁹,Zwart Wilbert⁴⁰^ORCID,Gilbert Luke A.¹²⁵⁴¹,Maher Christopher A.³¹⁴²⁴³⁴⁴^ORCID,Boutros Paul C.¹⁰⁴⁵⁴⁶^ORCID,Chi Kim N.⁷^ORCID,Ashworth Alan¹⁸^ORCID,Small Eric J.¹⁸,He Housheng H.¹⁰¹¹^ORCID,Wyatt Alexander W.⁷⁴⁷^ORCID,Quigley David A.¹²⁵⁴⁸^ORCID,Feng Felix Y.¹²⁸²⁵^ORCID

Affiliation:

1. 1Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.

2. 2Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA.

3. 3Division of Oncology, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden.

4. 4Department of Human Oncology, University of Wisconsin-Madison, Madison, WI.

5. 5William S. Middleton Memorial Veterans’ Hospital, Madison, WI.

6. 6Bluestar Genomics Inc., San Diego, CA.

7. 7Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.

8. 8Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA.

9. 9BC Cancer, Vancouver, BC, Canada.

10. 10Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

11. 11Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

12. 12Department of Automation, Xiamen University, Xiamen, Fujian, China.

13. 13Department of Surgery, University of Toronto, Toronto, Ontario, Canada.

14. 14Division of Hematology and Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI.

15. 15Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

16. 16Knight Cancer Institute, Oregon Health and Science University, Portland, OR.

17. 17Department of Pathology, Oregon Health & Science University, Portland, OR.

18. 18Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA.

19. 19University of Washington, Seattle, WA.

20. 20Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere, Finland.

21. 21Departments of Medicine, Hematology/Oncology and Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.

22. 22Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA.

23. 23VA Greater Los Angeles Healthcare System, Los Angeles, CA.

24. 24Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.

25. 25Department of Urology, University of California, San Francisco, San Francisco, CA.

26. 26Department of Anatomy, University of California, San Francisco, San Francisco, CA.

27. 27Department of Pathology, University of Pittsburgh, Pittsburgh, PA.

28. 28Department of Translational Medicine, Medical Faculty, Lund University, Malmö, Sweden.

29. 29Department of Urology, Skåne University Hospital, Malmö, Sweden.

30. 30Department of Medicine, University of Wisconsin-Madison, Madison, WI.

31. 31Siteman Cancer Center, Washington University, St. Louis, MO.

32. 32Division of Hematology Oncology, Department of Internal Medicine, University of California Davis, Sacramento, CA.

33. 33Comprehensive Cancer Center, University of California Davis, Sacramento, CA.

34. 34Department of Urologic Surgery, University of California Davis, Sacramento, CA.

35. 35Department of Radiation Oncology, University of Maryland, College Park, Baltimore, MD.

36. 36Urologic Oncology Program & Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA.

37. 37Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL.

38. 38Howard Hughes Medical Institute, University of Chicago, Chicago, IL.

39. 39Department of Pathology, Duke University, Durham, NC.

40. 40Netherlands Cancer Institute, Oncode Institute, Amsterdam, the Netherlands.

41. 41Arc Institute, Palo Alto, CA.

42. 42McDonnell Genome Institute, Washington University, St. Louis, MO.

43. 43Department of Internal Medicine, Washington University, St. Louis, MO.

44. 44Department of Biomedical Engineering, Washington University, St. Louis, MO.

45. 45Department of Human Genetics, Institute for Precision Health, UCLA, Los Angeles, CA.

46. 46Jonsson Comprehensive Cancer Center, Departments of Human Genetics and Urology, University of California Los Angeles, Los Angeles, CA.

47. 47Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada.

48. 48Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA.

Abstract

Abstract 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. 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

Funder

Stand Up To Cancer

Prostate Cancer Foundation

American Association for Cancer Research

Movember Foundation

Vetenskapsrådet

Svenska Läkaresällskapet

U.S. Department of Defense

National Institutes of Health

University of Wisconsin Carbone Cancer Center

National Cancer Institute

Safeway Foundation