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.
Nature genetics. 2024 Jul 17 [Epub ahead of print]
Shuang G Zhao, Matthew Bootsma, Stanley Zhou, Raunak Shrestha, Thaidy Moreno-Rodriguez, Arian Lundberg, Chu Pan, Christopher Arlidge, James R Hawley, Adam Foye, Alana S Weinstein, Martin Sjöström, Meng Zhang, Haolong Li, Lisa N Chesner, Nicholas R Rydzewski, Kyle T Helzer, Yue Shi, West Coast Dream Team Consortium , Molly Lynch, Scott M Dehm, Joshua M Lang, Joshi J Alumkal, Hansen H He, Alexander W Wyatt, Rahul Aggarwal, Wilbert Zwart, Eric J Small, David A Quigley, Mathieu Lupien, Felix Y Feng
Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA., Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA., Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA., Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA., Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA., Department of Internal Medicine, Division of Hematology-Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA., Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada., Netherlands Cancer Institute, Oncode Institute, Amsterdam, the Netherlands., Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA. .