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 Fraser; Lisa 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

doi:10.1158/0008-5472.CAN-22-1123

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

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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 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 language	English
Pages (from-to)	3888-3902
Number of pages	15
Journal	Cancer research
Volume	82
Issue number	21
DOIs	https://doi.org/10.1158/0008-5472.CAN-22-1123
State	Published - Nov 1 2022

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10.1158/0008-5472.CAN-22-1123

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Sjostrom, M., Zhao, S. G., Levy, S., Zhang, M., Ning, Y., Shrestha, R., Lundberg, A., Herberts, C., Foye, A., Aggarwal, R., Hua, J. T., Li, H., Bergamaschi, A., Maurice-Dro, C., Maheshwari, A., Chen, S., Ng, S. W. S., Ye, W., Petricca, J., ... Feng, F. Y. (2022). The 5-Hydroxymethylcytosine Landscape of Prostate Cancer. Cancer research, 82(21), 3888-3902. https://doi.org/10.1158/0008-5472.CAN-22-1123

@article{248eca108b494d1283ffc0f531270b4f,

title = "The 5-Hydroxymethylcytosine Landscape of Prostate Cancer",

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 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.",

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

note = "Funding Information: This research grant was administered by the American Association for Cancer Research, the scientific partner of SU2C. M. Sj{\"o}str{\"o}m was supported by the Swedish Research Council (Vetenskapsra det) with grant number 2018-00382, the Swedish Society of Medicine (Svenska L{\"a}kares{\"a}llskapet), and a Prostate Cancer Foundation Young Investigator Award. S.G. Zhao was funded by a Prostate Cancer Foundation Young Investigator Award, DOD W81XWH2110205, NIH 1DP2CA271832-01, and is a UW Carbone Cancer Center Ride Scholar. R. Aggarwal was funded by a Prostate Cancer Foundation Young Investigator Award. J.T. Hua was funded by a Prostate Cancer Foundation Young Investigator Award. J.J. Alumkal was supported by NIH/NCI 1R01 CA251245, NIH/NCI P50 CA097186, NIH/NCI P50 CA186786, NIH/NCI P50 CA186786-07S1, and Department of Defense Impact Award W81XWH-16-1-0597. H. Li was supported by a Prostate Cancer Foundation Young Investigator Award. L. Chesner was supported by a Prostate Cancer Foundation Young Investigator Award and a Department of Defense Prostate Cancer Research Program Early Investigator Research Award. J. Chou was funded by a Prostate Cancer Foundation Young Investigator Award and DOD award W81XWH20-1-0136. M.C. Haffner was supported by National Institutes of Health (NIH)/ National Cancer Institute (NCI) P50CA097186, the U.S. Department of Defense (DoD) W81XWH-20-1-0111, and the Safeway Foundation. M. Annala was funded by the Jane and Aatos Erkko Foundation. R. Bose was funded by a Prostate Cancer Foundation Young Investigator Award and NIH/NCI K08 1K08CA226348. J.M. Lang was funded by DOD W81XWH2110204. N.P. Mahajan is a recipient of NIH/NCI grants (1R01CA208258 and 5R01CA227025), Prostate Cancer Foundation (PCF) grant (17CHAL06), and Department of Defense award (PC200201). C. He was supported by grant NIH HG006827. L.A. Gilbert was supported by a Prostate Cancer Challenge Award, R01HG012227 and DP2CA239597, as well as the Goldberg-Benioff Endowed Professorship in Prostate Cancer Translational Biology. P.C. Boutros 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). A. Ashworth was supported by the Benioff Initiative in Prostate Cancer Research. H.H. He was supported by Prostate Cancer Canada (TAG2018-2061), CIHR operating grants (142246, 152863, 152864 and 159567), and Terry Fox New Frontiers Program Project Grant (1090 P3). H.H. He holds Joey and Toby Tanenbaum Brazilian Ball Chair in Prostate Cancer. D.A. Quigley was funded by Prostate Cancer Foundation Young Investigator and Challenge Awards and the UCSF Benioff Initiative for Prostate Cancer Research. F.Y. Feng was funded by Prostate Cancer Foundation Challenge Awards. Additional funding was provided by a UCSF Benioff Initiative for Prostate Cancer Research award. F.Y. Feng was supported by NIH/NCI 1R01CA230516-01, 1R01CA227025, and by NIH P50CA186786. F.Y. Feng was supported by Department of Defense grant W81XWH-19-1-0682. Funding Information: The authors thank the patients who selflessly contributed samples to this study and without whom this research would not have been possible. This research was supported by a Stand Up To Cancer-Prostate Cancer Foundation Prostate Cancer Dream Team Award (SU2C-AACR-DT0812 to E.J. Small) and by the Movember Foundation. Stand Up To Cancer is a division of the Entertainment Industry Funding Information: Foundation. This research grant was administered by the American Association for Cancer Research, the scientific partner of SU2C. M. Sjostrom was supported by the Swedish Research Council (Vetenskapsra°det) with grant number 2018-00382, the Swedish Society of Medicine (Svenska L€akares€allskapet), and a Prostate Cancer Foundation Young Investigator Award. S.G. Zhao was funded by a Prostate Cancer Foundation Young Investigator Award, DOD W81XWH2110205, NIH 1DP2CA271832-01, and is a UW Carbone Cancer Center Ride Scholar. R. Aggarwal was funded by a Prostate Cancer Foundation Young Investigator Award. J.T. Hua was funded by a Prostate Cancer Foundation Young Investigator Award. J.J. Alumkal was supported by NIH/NCI 1R01 CA251245, NIH/NCI P50 CA097186, NIH/NCI P50 CA186786, NIH/NCI P50 CA186786-07S1, and Department of Defense Impact Award W81XWH-16-1-0597. H. Li was supported by a Prostate Cancer Foundation Young Investigator Award. L. Chesner was supported by a Prostate Cancer Foundation Young Investigator Award and a Department of Defense Prostate Cancer Research Program Early Investigator Research Award. J. Chou was funded by a Prostate Cancer Foundation Young Investigator Award and DOD award W81XWH-20-1-0136. M.C. Haffner was supported by National Institutes of Health (NIH)/ National Cancer Institute (NCI) P50CA097186, the U.S. Department of Defense (DoD) W81XWH-20-1-0111, and the Safeway Foundation. M. Annala was funded by the Jane and Aatos Erkko Foundation. R. Bose was funded by a Prostate Cancer Foundation Young Investigator Award and NIH/NCI K08 1K08CA226348. J.M. Lang was funded by DOD W81XWH2110204. N.P. Mahajan is a recipient of NIH/NCI grants (1R01CA208258 and 5R01CA227025), Prostate Cancer Foundation (PCF) grant (17CHAL06), and Department of Defense award (PC200201). C. He was supported by grant NIH HG006827. L.A. Gilbert was supported by a Prostate Cancer Challenge Award, R01HG012227 and DP2CA239597, as well as the Goldberg-Benioff Publisher Copyright: {\textcopyright} 2022 The Authors.",

year = "2022",

month = nov,

day = "1",

doi = "10.1158/0008-5472.CAN-22-1123",

language = "English",

volume = "82",

pages = "3888--3902",

journal = "Cancer Research",

issn = "0008-5472",

number = "21",

}

Sjostrom, M, Zhao, SG, Levy, S, Zhang, M, Ning, Y, Shrestha, R, Lundberg, A, Herberts, C, Foye, A, Aggarwal, R, Hua, JT, Li, H, Bergamaschi, A, Maurice-Dro, C, Maheshwari, A, Chen, S, Ng, SWS, Ye, W, Petricca, J, Fraser, M, Chesner, L, Perry, MD, Moreno-Rodrigue, T, Chen, WS, Alumkal, JJ, Chou, J, Morgans, AK, Beer, TM, Thomas, GV, Gleave, M, Lloyd, P, Phillips, T, McCarthy, E, Haffner, MC, Zoubeidi, A, Annala, M, Reiter, RE, Rettig, MB, Witte, ON, Fong, L, Bose, R, Huang, FW, Luo, J, Bjartell, A, Lang, JM, Mahajan, NP, Lara, PN, Evans, CP, Tran, PT, Posadas, EM, He, C, Cui, XL, Huang, J, Zwart, W, Gilbert, LA, Maher, CA, Boutros, PC, Chi, KN, Ashworth, A, Small, EJ, He, HH, Wyatt, AW, Quigley, DA & Feng, FY 2022, 'The 5-Hydroxymethylcytosine Landscape of Prostate Cancer', Cancer research, vol. 82, no. 21, pp. 3888-3902. https://doi.org/10.1158/0008-5472.CAN-22-1123

TY - JOUR

T1 - The 5-Hydroxymethylcytosine Landscape of Prostate Cancer

AU - Sjostrom, Martin

AU - Zhao, Shuang G.

AU - Levy, Samuel

AU - Zhang, Meng

AU - Ning, Yuhong

AU - Shrestha, Raunak

AU - Lundberg, Arian

AU - Herberts, Cameron

AU - Foye, Adam

AU - Aggarwal, Rahul

AU - Hua, Junjie T.

AU - Li, Haolong

AU - Bergamaschi, Anna

AU - Maurice-Dro, Corinne

AU - Maheshwari, Ashutosh

AU - Chen, Sujun

AU - Ng, Sarah W.S.

AU - Ye, Wenbin

AU - Petricca, Jessica

AU - Fraser, Michael

AU - Chesner, Lisa

AU - Perry, Marc D.

AU - Moreno-Rodrigue, Thaidy

AU - Chen, William S.

AU - Alumkal, Joshi J.

AU - Chou, Jonathan

AU - Morgans, Alicia K.

AU - Beer, Tomasz M.

AU - Thomas, George V.

AU - Gleave, Martin

AU - Lloyd, Paul

AU - Phillips, Tierney

AU - McCarthy, Erin

AU - Haffner, Michael C.

AU - Zoubeidi, Amina

AU - Annala, Matti

AU - Reiter, Robert E.

AU - Rettig, Matthew B.

AU - Witte, Owen N.

AU - Fong, Lawrence

AU - Bose, Rohit

AU - Huang, Franklin W.

AU - Luo, Jianhua

AU - Bjartell, Anders

AU - Lang, Joshua M.

AU - Mahajan, Nupam P.

AU - Lara, Primo N.

AU - Evans, Christopher P.

AU - Tran, Phuoc T.

AU - Posadas, Edwin M.

AU - He, Chuan

AU - Cui, Xiao Long

AU - Huang, Jiaoti

AU - Zwart, Wilbert

AU - Gilbert, Luke A.

AU - Maher, Christopher A.

AU - Boutros, Paul C.

AU - Chi, Kim N.

AU - Ashworth, Alan

AU - Small, Eric J.

AU - He, Housheng H.

AU - Wyatt, Alexander W.

AU - Quigley, David A.

AU - Feng, Felix Y.

N1 - Funding Information: This research grant was administered by the American Association for Cancer Research, the scientific partner of SU2C. M. Sjöström was supported by the Swedish Research Council (Vetenskapsra det) with grant number 2018-00382, the Swedish Society of Medicine (Svenska Läkaresällskapet), and a Prostate Cancer Foundation Young Investigator Award. S.G. Zhao was funded by a Prostate Cancer Foundation Young Investigator Award, DOD W81XWH2110205, NIH 1DP2CA271832-01, and is a UW Carbone Cancer Center Ride Scholar. R. Aggarwal was funded by a Prostate Cancer Foundation Young Investigator Award. J.T. Hua was funded by a Prostate Cancer Foundation Young Investigator Award. J.J. Alumkal was supported by NIH/NCI 1R01 CA251245, NIH/NCI P50 CA097186, NIH/NCI P50 CA186786, NIH/NCI P50 CA186786-07S1, and Department of Defense Impact Award W81XWH-16-1-0597. H. Li was supported by a Prostate Cancer Foundation Young Investigator Award. L. Chesner was supported by a Prostate Cancer Foundation Young Investigator Award and a Department of Defense Prostate Cancer Research Program Early Investigator Research Award. J. Chou was funded by a Prostate Cancer Foundation Young Investigator Award and DOD award W81XWH20-1-0136. M.C. Haffner was supported by National Institutes of Health (NIH)/ National Cancer Institute (NCI) P50CA097186, the U.S. Department of Defense (DoD) W81XWH-20-1-0111, and the Safeway Foundation. M. Annala was funded by the Jane and Aatos Erkko Foundation. R. Bose was funded by a Prostate Cancer Foundation Young Investigator Award and NIH/NCI K08 1K08CA226348. J.M. Lang was funded by DOD W81XWH2110204. N.P. Mahajan is a recipient of NIH/NCI grants (1R01CA208258 and 5R01CA227025), Prostate Cancer Foundation (PCF) grant (17CHAL06), and Department of Defense award (PC200201). C. He was supported by grant NIH HG006827. L.A. Gilbert was supported by a Prostate Cancer Challenge Award, R01HG012227 and DP2CA239597, as well as the Goldberg-Benioff Endowed Professorship in Prostate Cancer Translational Biology. P.C. Boutros 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). A. Ashworth was supported by the Benioff Initiative in Prostate Cancer Research. H.H. He was supported by Prostate Cancer Canada (TAG2018-2061), CIHR operating grants (142246, 152863, 152864 and 159567), and Terry Fox New Frontiers Program Project Grant (1090 P3). H.H. He holds Joey and Toby Tanenbaum Brazilian Ball Chair in Prostate Cancer. D.A. Quigley was funded by Prostate Cancer Foundation Young Investigator and Challenge Awards and the UCSF Benioff Initiative for Prostate Cancer Research. F.Y. Feng was funded by Prostate Cancer Foundation Challenge Awards. Additional funding was provided by a UCSF Benioff Initiative for Prostate Cancer Research award. F.Y. Feng was supported by NIH/NCI 1R01CA230516-01, 1R01CA227025, and by NIH P50CA186786. F.Y. Feng was supported by Department of Defense grant W81XWH-19-1-0682. Funding Information: The authors thank the patients who selflessly contributed samples to this study and without whom this research would not have been possible. This research was supported by a Stand Up To Cancer-Prostate Cancer Foundation Prostate Cancer Dream Team Award (SU2C-AACR-DT0812 to E.J. Small) and by the Movember Foundation. Stand Up To Cancer is a division of the Entertainment Industry Funding Information: Foundation. This research grant was administered by the American Association for Cancer Research, the scientific partner of SU2C. M. Sjostrom was supported by the Swedish Research Council (Vetenskapsra°det) with grant number 2018-00382, the Swedish Society of Medicine (Svenska L€akares€allskapet), and a Prostate Cancer Foundation Young Investigator Award. S.G. Zhao was funded by a Prostate Cancer Foundation Young Investigator Award, DOD W81XWH2110205, NIH 1DP2CA271832-01, and is a UW Carbone Cancer Center Ride Scholar. R. Aggarwal was funded by a Prostate Cancer Foundation Young Investigator Award. J.T. Hua was funded by a Prostate Cancer Foundation Young Investigator Award. J.J. Alumkal was supported by NIH/NCI 1R01 CA251245, NIH/NCI P50 CA097186, NIH/NCI P50 CA186786, NIH/NCI P50 CA186786-07S1, and Department of Defense Impact Award W81XWH-16-1-0597. H. Li was supported by a Prostate Cancer Foundation Young Investigator Award. L. Chesner was supported by a Prostate Cancer Foundation Young Investigator Award and a Department of Defense Prostate Cancer Research Program Early Investigator Research Award. J. Chou was funded by a Prostate Cancer Foundation Young Investigator Award and DOD award W81XWH-20-1-0136. M.C. Haffner was supported by National Institutes of Health (NIH)/ National Cancer Institute (NCI) P50CA097186, the U.S. Department of Defense (DoD) W81XWH-20-1-0111, and the Safeway Foundation. M. Annala was funded by the Jane and Aatos Erkko Foundation. R. Bose was funded by a Prostate Cancer Foundation Young Investigator Award and NIH/NCI K08 1K08CA226348. J.M. Lang was funded by DOD W81XWH2110204. N.P. Mahajan is a recipient of NIH/NCI grants (1R01CA208258 and 5R01CA227025), Prostate Cancer Foundation (PCF) grant (17CHAL06), and Department of Defense award (PC200201). C. He was supported by grant NIH HG006827. L.A. Gilbert was supported by a Prostate Cancer Challenge Award, R01HG012227 and DP2CA239597, as well as the Goldberg-Benioff Publisher Copyright: © 2022 The Authors.

PY - 2022/11/1

Y1 - 2022/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85141889328&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-22-1123

DO - 10.1158/0008-5472.CAN-22-1123

M3 - Article

C2 - 36251389

AN - SCOPUS:85141889328

SN - 0008-5472

VL - 82

SP - 3888

EP - 3902

JO - Cancer Research

JF - Cancer Research

IS - 21

ER -

The 5-Hydroxymethylcytosine Landscape of Prostate Cancer

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