The 5-Hydroxymethylcytosine Landscape of Prostate Cancer.
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ICR Authors
Authors
Sjöström, 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-Dror, C
Maheshwari, A
Chen, S
Ng, SWS
Ye, W
Petricca, J
Fraser, M
Chesner, L
Perry, MD
Moreno-Rodriguez, 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, X-L
Huang, J
Zwart, W
Gilbert, LA
Maher, CA
Boutros, PC
Chi, KN
Ashworth, A
Small, EJ
He, HH
Wyatt, AW
Quigley, DA
Feng, FY
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-Dror, C
Maheshwari, A
Chen, S
Ng, SWS
Ye, W
Petricca, J
Fraser, M
Chesner, L
Perry, MD
Moreno-Rodriguez, 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, X-L
Huang, J
Zwart, W
Gilbert, LA
Maher, CA
Boutros, PC
Chi, KN
Ashworth, A
Small, EJ
He, HH
Wyatt, AW
Quigley, DA
Feng, FY
Document Type
Journal Article
Date
2022-11-02
Date Accepted
2022-07-29
Abstract
UNLABELLED: 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.
Citation
Cancer Research, 2022, 82 (21), pp. 3888 - 3902
Source Title
Cancer Research
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
0008-5472
eISSN
1538-7445
1538-7445
1538-7445
Collections
Research Team
Cancer Biomarkers