Integrated analyses highlight interactions between the three-dimensional genome and DNA, RNA and epigenomic alterations in metastatic prostate cancer
(2024) In Nature Genetics 56(8). p.1689-1700- Abstract
The impact of variations in the three-dimensional structure of the genome has been recognized, but solid cancer tissue studies are limited. Here, we performed integrated deep Hi-C sequencing with matched whole-genome sequencing, whole-genome bisulfite sequencing, 5-hydroxymethylcytosine (5hmC) sequencing and RNA sequencing across a cohort of 80 biopsy samples from patients with metastatic castration-resistant prostate cancer. Dramatic differences were present in gene expression, 5-methylcytosine/5hmC methylation and in structural variation versus mutation rate between A and B (open and closed) chromatin compartments. A subset of tumors exhibited depleted regional chromatin contacts at the AR locus, linked to extrachromosomal circular... (More)
The impact of variations in the three-dimensional structure of the genome has been recognized, but solid cancer tissue studies are limited. Here, we performed integrated deep Hi-C sequencing with matched whole-genome sequencing, whole-genome bisulfite sequencing, 5-hydroxymethylcytosine (5hmC) sequencing and RNA sequencing across a cohort of 80 biopsy samples from patients with metastatic castration-resistant prostate cancer. Dramatic differences were present in gene expression, 5-methylcytosine/5hmC methylation and in structural variation versus mutation rate between A and B (open and closed) chromatin compartments. A subset of tumors exhibited depleted regional chromatin contacts at the AR locus, linked to extrachromosomal circular DNA (ecDNA) and worse response to AR signaling inhibitors. We also identified topological subtypes associated with stark differences in methylation structure, gene expression and prognosis. Our data suggested that DNA interactions may predispose to structural variant formation, exemplified by the recurrent TMPRSS2-ERG fusion. This comprehensive integrated sequencing effort represents a unique clinical tumor resource.
(Less)
- author
- author collaboration
- publishing date
- 2024-08
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Humans, Male, DNA Methylation, 5-Methylcytosine/analogs & derivatives, Gene Expression Regulation, Neoplastic, Epigenomics/methods, Neoplasm Metastasis/genetics, Genome, Human, Prostatic Neoplasms/genetics, Epigenesis, Genetic, Receptors, Androgen/genetics, Chromatin/genetics, Prostatic Neoplasms, Castration-Resistant/genetics, Oncogene Proteins, Fusion/genetics, DNA/genetics, Whole Genome Sequencing, RNA/genetics, Prognosis
- in
- Nature Genetics
- volume
- 56
- issue
- 8
- pages
- 1689 - 1700
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:39020220
- scopus:85202476342
- ISSN
- 1546-1718
- DOI
- 10.1038/s41588-024-01826-3
- language
- English
- LU publication?
- no
- additional info
- © 2024. The Author(s).
- id
- a831c5d6-0b88-4ae2-bc23-18977d0c78b7
- date added to LUP
- 2026-02-18 08:39:26
- date last changed
- 2026-02-19 04:01:04
@article{a831c5d6-0b88-4ae2-bc23-18977d0c78b7,
abstract = {{<p>The impact of variations in the three-dimensional structure of the genome has been recognized, but solid cancer tissue studies are limited. Here, we performed integrated deep Hi-C sequencing with matched whole-genome sequencing, whole-genome bisulfite sequencing, 5-hydroxymethylcytosine (5hmC) sequencing and RNA sequencing across a cohort of 80 biopsy samples from patients with metastatic castration-resistant prostate cancer. Dramatic differences were present in gene expression, 5-methylcytosine/5hmC methylation and in structural variation versus mutation rate between A and B (open and closed) chromatin compartments. A subset of tumors exhibited depleted regional chromatin contacts at the AR locus, linked to extrachromosomal circular DNA (ecDNA) and worse response to AR signaling inhibitors. We also identified topological subtypes associated with stark differences in methylation structure, gene expression and prognosis. Our data suggested that DNA interactions may predispose to structural variant formation, exemplified by the recurrent TMPRSS2-ERG fusion. This comprehensive integrated sequencing effort represents a unique clinical tumor resource.</p>}},
author = {{Zhao, Shuang G and Bootsma, Matthew and Zhou, Stanley and Shrestha, Raunak and Moreno-Rodriguez, Thaidy and Lundberg, Arian and Pan, Chu and Arlidge, Christopher and Hawley, James R and Foye, Adam and Weinstein, Alana S and Sjöström, Martin and Zhang, Meng and Li, Haolong and Chesner, Lisa N and Rydzewski, Nicholas R and Helzer, Kyle T and Shi, Yue and Lynch, Molly and Dehm, Scott M and Lang, Joshua M and Alumkal, Joshi J and He, Hansen H and Wyatt, Alexander W and Aggarwal, Rahul and Zwart, Wilbert and Small, Eric J and Quigley, David A and Lupien, Mathieu and Feng, Felix Y}},
issn = {{1546-1718}},
keywords = {{Humans; Male; DNA Methylation; 5-Methylcytosine/analogs & derivatives; Gene Expression Regulation, Neoplastic; Epigenomics/methods; Neoplasm Metastasis/genetics; Genome, Human; Prostatic Neoplasms/genetics; Epigenesis, Genetic; Receptors, Androgen/genetics; Chromatin/genetics; Prostatic Neoplasms, Castration-Resistant/genetics; Oncogene Proteins, Fusion/genetics; DNA/genetics; Whole Genome Sequencing; RNA/genetics; Prognosis}},
language = {{eng}},
number = {{8}},
pages = {{1689--1700}},
publisher = {{Nature Publishing Group}},
series = {{Nature Genetics}},
title = {{Integrated analyses highlight interactions between the three-dimensional genome and DNA, RNA and epigenomic alterations in metastatic prostate cancer}},
url = {{http://dx.doi.org/10.1038/s41588-024-01826-3}},
doi = {{10.1038/s41588-024-01826-3}},
volume = {{56}},
year = {{2024}},
}