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The 5-Hydroxymethylcytosine Landscape of Prostate Cancer

Sjostrom, M. LU ; Bjartell, A. LU and Feng, F.Y. (2022) In Cancer Research 82(21). p.3888-3902
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... (More)
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. © 2022 The Authors. (Less)
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keywords
5 hydroxymethylcytosine, DNA, transcriptome, 5 methylcytosine, 5-hydroxymethylcytosine, Article, cancer cell, cancer growth, cancer tissue, cell dedifferentiation, cell proliferation, controlled study, disease course, DNA methylation, genome, human, human tissue, major clinical study, male, metastatic castration resistant prostate cancer, prognosis, sequence analysis, transcriptomics, whole genome bisulfite sequencing, biopsy, prostate, prostate tumor, 5-Methylcytosine, Biopsy, Humans, Male, Prostate, Prostatic Neoplasms
in
Cancer Research
volume
82
issue
21
pages
15 pages
publisher
American Association for Cancer Research Inc.
external identifiers
  • scopus:85141889328
  • pmid:36251389
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-22-1123
language
English
LU publication?
yes
id
6f0832ba-ad86-4a06-a0b8-a05605537708
date added to LUP
2023-01-11 15:35:29
date last changed
2023-01-12 03:00:04
@article{6f0832ba-ad86-4a06-a0b8-a05605537708,
  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. © 2022 The Authors.}},
  author       = {{Sjostrom, M. and Bjartell, A. and Feng, F.Y.}},
  issn         = {{0008-5472}},
  keywords     = {{5 hydroxymethylcytosine; DNA; transcriptome; 5 methylcytosine; 5-hydroxymethylcytosine; Article; cancer cell; cancer growth; cancer tissue; cell dedifferentiation; cell proliferation; controlled study; disease course; DNA methylation; genome; human; human tissue; major clinical study; male; metastatic castration resistant prostate cancer; prognosis; sequence analysis; transcriptomics; whole genome bisulfite sequencing; biopsy; prostate; prostate tumor; 5-Methylcytosine; Biopsy; Humans; Male; Prostate; Prostatic Neoplasms}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{21}},
  pages        = {{3888--3902}},
  publisher    = {{American Association for Cancer Research Inc.}},
  series       = {{Cancer Research}},
  title        = {{The 5-Hydroxymethylcytosine Landscape of Prostate Cancer}},
  url          = {{http://dx.doi.org/10.1158/0008-5472.CAN-22-1123}},
  doi          = {{10.1158/0008-5472.CAN-22-1123}},
  volume       = {{82}},
  year         = {{2022}},
}