The 5-Hydroxymethylcytosine Landscape of Prostate Cancer

被引：35

作者：

Sjostrom, Martin ^{[1
,2
,3
]}

Zhao, Shuang G. ^{[4
,5
]}

Levy, Samuel ^{[6
]}

Zhang, Meng ^{[1
,2
]}

Ning, Yuhong ^{[6
]}

Shrestha, Raunak ^{[1
,2
]}

Lundberg, Arian ^{[1
,2
]}

Herberts, Cameron ^{[7
]}

Foye, Adam ^{[1
,8
]}

Aggarwal, Rahul ^{[1
,8
]}

Hua, Junjie T. ^{[1
,2
]}

Li, Haolong ^{[1
,2
]}

Bergamaschi, Anna ^{[6
]}

Maurice-Dror, Corinne ^{[7
,9
]}

Maheshwari, Ashutosh ^{[1
,2
]}

Chen, Sujun ^{[10
,11
]}

Ng, Sarah W. S. ^{[7
]}

Ye, Wenbin ^{[10
,11
,12
]}

Petricca, Jessica ^{[10
,11
]}

Fraser, Michael ^{[11
,13
]}

Chesner, Lisa ^{[1
,2
]}

Perry, Marc D. ^{[1
,2
]}

Moreno-Rodriguez, Thaidy ^{[1
,2
]}

Chen, William S. ^{[1
,2
]}

Alumkal, Joshi J. ^{[14
]}

Chou, Jonathan ^{[1
,8
]}

Morgans, Alicia K. ^{[15
]}

Beer, Tomasz M. ^{[16
]}

Thomas, George, V ^{[16
,17
]}

Gleave, Martin ^{[7
]}

Lloyd, Paul ^{[6
]}

Phillips, Tierney ^{[6
]}

McCarthy, Erin ^{[6
]}

Haffner, Michael C. ^{[18
,19
,20
]}

Zoubeidi, Amina ^{[7
]}

Annala, Matti ^{[7
,21
,22
]}

Reiter, Robert E. ^{[23
,24
,25
,26
]}

Rettig, Matthew B. ^{[23
,24
,25
,26
,27
]}

Witte, Owen N. ^{[28
]}

Fong, Lawrence ^{[1
,8
]}

Bose, Rohit ^{[1
,8
,29
,30
]}

Huang, Franklin W. ^{[1
,8
]}

Luo, Jianhua ^{[31
]}

Bjartell, Anders ^{[32
,33
]}

Lang, Joshua M. ^{[34
]}

Mahajan, Nupam P. ^{[35
]}

Lara, Primo N. ^{[36
,37
]}

Evans, Christopher P. ^{[37
,38
]}

Tran, Phuoc T. ^{[39
]}

Posadas, Edwin M. ^{[40
,41
]}

机构：

[1] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

[2] Univ Calif San Francisco, Dept Radiat Oncol, Box 3110,Room 450,1450 3rd St, San Francisco, CA 94158 USA

[3] Lund Univ, Fac Med, Dept Clin Sci Lund, Div Oncol, Lund, Sweden

[4] Univ Wisconsin Madison, Dept Human Oncol, Madison, WI USA

[5] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA

[6] Bluestar Genom Inc, San Diego, CA USA

[7] Univ British Columbia, Vancouver Prostate Ctr, Dept Urol Sci, Vancouver, BC, Canada

[8] Univ Calif San Francisco, Dept Med, Div Hematol & Oncol, San Francisco, CA 94143 USA

[9] BC Canc, Vancouver, BC, Canada

[10] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

[11] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada

[12] Xiamen Univ, Dept Automat, Xiamen, Fujian, Peoples R China

[13] Univ Toronto, Dept Surg, Toronto, ON, Canada

[14] Univ Michigan, Div Hematol & Oncol, Rogel Canc Ctr, Ann Arbor, MI 48109 USA

[15] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA

[16] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA

[17] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA

[18] Fred Hutchinson Canc Res Ctr, Div Human Biol, 1124 Columbia St, Seattle, WA 98104 USA

[19] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA

[20] Univ Washington, Seattle, WA 98195 USA

[21] Tampere Univ, Fac Med & Hlth Technol, Tampere, Finland

[22] Tays Canc Ctr, Tampere, Finland

[23] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA

[24] Univ Calif Los Angeles, David Geffen Sch Med, Dept Hematol Oncol, Los Angeles, CA 90095 USA

[25] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA

[26] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA

[27] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA

[28] Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA

[29] Univ Calif San Francisco, Dept Urol, San Francisco, CA USA

[30] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA

[31] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA

[32] Lund Univ, Med Fac, Dept Translat Med, Malmo, Sweden

[33] Skane Univ Hosp, Dept Urol, Malmo, Sweden

[34] Univ Wisconsin Madison, Dept Med, Madison, WI USA

[35] Washington Univ, Siteman Canc Ctr, St Louis, MO 63110 USA

[36] Univ Calif Davis, Dept Internal Med, Div Hematol Oncol, Sacramento, CA 95817 USA

[37] Univ Calif Davis, Comprehens Canc Ctr, Sacramento, CA 95817 USA

[38] Univ Calif Davis, Dept Urol Surg, Sacramento, CA 95817 USA

[39] Univ Maryland, Dept Radiat Oncol, Baltimore, MD 21201 USA

[40] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Urol Oncol Program, Los Angeles, CA 90048 USA

[41] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Urooncol Res Labs, Los Angeles, CA 90048 USA

[42] Univ Chicago, Dept Biochem & Mol Biol, Dept Chem, Inst Biophys Dynam, 920 E 58Th St, Chicago, IL 60637 USA

[43] Univ Chicago, Howard Hughes Med Inst, 5841 S Maryland Ave, Chicago, IL 60637 USA

[44] Duke Univ, Dept Pathol, Durham, NC 27706 USA

[45] Netherlands Canc Inst, Oncode Inst, Amsterdam, Netherlands

[46] Arc Inst, Palo Alto, CA USA

[47] Washington Univ, McDonnell Genome Inst, St Louis, MO 63110 USA

[48] Washington Univ, Dept Internal Med, St Louis, MO 63110 USA

[49] Washington Univ, Dept Biomed Engn, St Louis, MO 63110 USA

[50] Univ Calif Los Angeles, Dept Human Genet, Inst Precis Hlth, Los Angeles, CA USA

来源：

CANCER RESEARCH | 2022年 / 82卷 / 21期

基金：

瑞典研究理事会;

关键词：

GENE FUSIONS; DNA; TRANSFORMATION; TRANSCRIPTION; INFORMATION; SIGNATURES; RECEPTOR;

D O I：

10.1158/0008-5472.CAN-22-1123

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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-hydroxy-methylcytosine (5hmC) is associated with transcriptional acti-vation. 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 epige-nomic 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.

引用

页码：3888 / 3902

页数：15

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