The 5-Hydroxymethylcytosine Landscape of Prostate Cancer
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/6f0832ba-ad86-4a06-a0b8-a05605537708
- author
- Sjostrom, M. LU ; Bjartell, A. LU and Feng, F.Y.
- author collaboration
- organization
-
- Breast cancer treatment
- LUCC: Lund University Cancer Centre
- Personalized Breast Cancer Treatment (research group)
- Breast cancer Proteogenomics (research group)
- Urological cancer, Malmö (research group)
- eSSENCE: The e-Science Collaboration
- EpiHealth: Epidemiology for Health
- Division of Translational Cancer Research
- publishing date
- 2022-11-01
- type
- Contribution to journal
- publication status
- published
- subject
- 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}}, }