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The landscape of prostate tumour methylation

Arbet, J.
; 
Yamaguchi, T. N.
; 
Shiah, Y. J.
; 
Hugh-White, R.
; 
Wiggins, A.
; 
Oh, J.
; 
Gebo, T.
; 
Foucal, A.
; 
Lesurf, R.
; 
Jung, C. H.
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Abstract
Prostate cancer is characterized by profound clinical and molecular heterogeneity. While its genomic heterogeneity is well-characterized, its epigenomic heterogeneity remains less understood. We therefore created a compendium of 3,001 multi-ancestry prostate methylomes spanning normal tissue through localized disease of all grades to poly-metastatic disease. A subset of 884 samples had multi-omic DNA and/or RNA characterization. We identify four epigenomic subtypes that risk-stratify patients and reflect distinct evolutionary trajectories. We demonstrate extensive regulatory interplay between DNA ploidy and DNA methylation, with transcriptional consequences that vary across genes and disease stages. We define the epigenetic dysregulation signatures of the 15 most important clinico-molecular features, creating predictive models for each. For example, we identify specific epigenetic features that predict patient outcome and that are synergistic with clinico-genomic prognostic features. These results define a complex interplay between tumour genetics and epigenetics that converges to modify gene-expression programs and clinical presentation.
Authors
Arbet, J.
Yamaguchi, T. N.
Shiah, Y. J.
Hugh-White, R.
Wiggins, A.
Oh, J.
Gebo, T.
Foucal, A.
Lesurf, R.
Jung, C. H.
Dang, R. M. A.
Agrawal, R.
Livingstone, J.
Salcedo, A.
Yao, C. Q.
Espiritu, S. M. G.
Houlahan, K. E.
Yousif, F.
Heisler, L. E.
Papenfuss, A. T.
Fraser, M.
Pope, B.
Kishan, A.
Berlin, A.
Chua, M. L. K.
Corcoran, N. M.
van der Kwast, T.
Hovens, C. M.
Bristow, R. G.
Boutros, P. C.
Affiliation
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California. Institute for Precision Health, University of California, Los Angeles, California. Department of Human Genetics, University of California, Los Angeles, California. Department of Urology, David Geffen School of Medicine, University of California, California. Ontario Institute for Cancer Research, Toronto, Canada. Department of Mathematics and Statistics, Carleton College, Northfield, MN. Melbourne Bioinformatics, University of Melbourne, Parkville, Australia. Department of Medical Biophysics, University of Toronto, Toronto, Canada. Walter and Eliza Hall Institute of Medical Research, Parkville, Australia. Department of Medical Biology, University of Melbourne, Parkville, Australia. Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. Australian BioCommons, University of Melbourne, Parkville, Australia. Department of Surgery, University of Melbourne, Parkville, Australia. Department of Radiation Oncology, University of California, Los Angeles. Department of Radiation Oncology, University of Toronto, Toronto, Canada. Divisions of Radiation Oncology and Medical Sciences, National Cancer Centre Singapore, Singapore. Duke-NUS Medical School, Singapore. Department of Urology, Western Health, Footscray, Australia. Department of Urology, Royal Melbourne Hospital, Parkville, Australia. Victorian Comprehensive Cancer Centre, Parkville, Australia. CRUK Manchester Institute and Manchester Cancer Research Centre, Division of Cancer Sciences-FBMH, University of Manchester, UK.
Description
Date
2025
Publisher
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All Paterson Institute for Cancer Research
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Preprint
Citation
Arbet J, Yamaguchi TN, Shiah YJ, Hugh-White R, Wiggins A, Oh J, et al. The Landscape of Prostate Tumour Methylation. BioRxiv : the preprint server for biology. 2025 Apr 28. PubMed PMID: 39990314. Pubmed Central PMCID: PMC11844408 submitted work: personal fees from Astellas, Axiom, Bicara Therapeutics, IQVIA, Janssen, MSD, Seagen, Varian; non-financial support from Veracyte Inc; personal fees and grants from Bayer; personal fees and grants from BeiGene; consults for Bicara Therapeutics; consults for ImmunoScape; consults for PVMed; consults for Varian Thought Leadership Council; and is a co-inventor of the patent of a High Sensitivity Lateral Flow Immunoassay For Detection of Analyte in Sample (10202107837T), Singapore, and serves on the Board of Directors of Digital Life Line Pte Ltd that owns the licensing agreement of the patent. PCB sits on the Scientific Advisory Board of Intersect Diagnostics Inc., and formerly sat on those of Sage Bionetworks and of BioSymetrics Inc. Epub 2025/02/24. eng.
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https://christie.openrepository.com/handle/10541/628174
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