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The landscape of N(6)-methyladenosine in localized primary prostate cancer

Xu, X.
; 
Zhu, H.
; 
Hugh-White, R.
; 
Livingstone, J.
; 
Eng, S.
; 
Zeltser, N.
; 
Wang, Y.
; 
Pajdzik, K.
; 
Chen, S.
; 
Houlahan, K. E.
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Abstract
N(6)-methyladenosine (m(6)A), the most abundant internal RNA modification in humans, regulates most aspects of RNA processing. Prostate cancer is characterized by widespread transcriptomic dysregulation; therefore, we characterized the m(6)A landscape of 162 localized prostate tumors with matched DNA, RNA and protein profiling. m(6)A abundance varied dramatically across tumors, with global patterns emerging via complex germline-somatic cooperative regulation. Individual germline polymorphisms regulated m(6)A abundance, cooperating with somatic mutation of cancer driver genes and m(6)A regulators. The resulting complex patterns were associated with prognostic clinical features and established the biomarker potential of global and locus-specific m(6)A patterns. Tumor hypoxia dysregulates m(6)A profiles, bridging prior genomic and proteomic observations. Specific m(6)A sites, such as those in VCAN, drive disease aggression, associating with poor outcomes, tumor growth and metastasis. m(6)A dysregulation is thus associated with key events in the natural history of prostate cancer: germline risk, microenvironmental dysregulation, somatic mutation and metastasis.
Authors
Xu, X.
Zhu, H.
Hugh-White, R.
Livingstone, J.
Eng, S.
Zeltser, N.
Wang, Y.
Pajdzik, K.
Chen, S.
Houlahan, K. E.
Luo, W.
Liu, S.
Xu, X.
Sheng, M.
Guo, W. Y.
Arbet, J.
Song, Y.
Wang, M.
Zeng, Y.
Wang, S.
Zhu, G.
Gao, T.
Chen, W.
Ci, X.
Xu, W.
Xu, K.
Orain, M.
Picard, V.
Hovington, H.
Bergeron, A.
Lacombe, L.
Têtu, B.
Fradet, Y.
Lupien, M.
Wei, G. H.
Koritzinsky, M.
Bristow, R. G.
Fleshner, N. E.
Wu, X.
Shao, Y.
He, C.
Berlin, A.
van der Kwast, T.
Leong, H.
Boutros, P. C.
He, H. H.
Affiliation
Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Vector Institute, Toronto, Ontario, Canada. Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA. Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, Los Angeles, CA, USA. Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA. Department of Chemistry, the University of Chicago, Chicago, IL, USA. Howard Hughes Medical Institute, the University of Chicago, Chicago, IL, USA. West China School of Public Health, West China Fourth Hospital and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China. Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. Sunnybrook Research Institute, Toronto, Ontario, Canada. Institute of Precision Medicine, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Department of Respiratory and Critical Care Medicine, the Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China. MOE Key Laboratory of Metabolism and Molecular Medicine and Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences and Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai, China. Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. Research Centre of CHU de Québec-Université Laval, Québec City, Quebec, Canada. State Key Laboratory of Common Mechanism Research for Major Disease, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, China. Division of Cancer Sciences, University of Manchester, Manchester, UK. Christie NHS Trust and CRUK Manchester Institute and Cancer Centre, Manchester, UK. Geneseeq Research Institute, Geneseeq Technology lnc., Toronto, Ontario, Canada. School of Public Health, Nanjing Medical University, Nanjing, China. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. pboutros@mednet.ucla.edu. Vector Institute, Toronto, Ontario, Canada. pboutros@mednet.ucla.edu. Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA. pboutros@mednet.ucla.edu. Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA. pboutros@mednet.ucla.edu. Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, Los Angeles, CA, USA. pboutros@mednet.ucla.edu. Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA. pboutros@mednet.ucla.edu. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. pboutros@mednet.ucla.edu. Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. hansenhe@uhnresearch.ca. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. hansenhe@uhnresearch.ca.
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2025
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Xu X, Zhu H, Hugh-White R, Livingstone J, Eng S, Zeltser N, et al. The landscape of N(6)-methyladenosine in localized primary prostate cancer. Nature genetics. 2025 Apr;57(4):934-48. PubMed PMID: 40128621. Pubmed Central PMCID: PMC11985349 paper, H.Z. was an employee at Deep Genomics. All contributions to the design, analysis and interpretation of results of this project were completed outside of the term of employment. P.C.B. sits on the scientific advisory boards of Sage Bionetworks, Intersect Diagnostics and BioSymetrics. Y. Shao and X.W. are shareholders and/or employees of Geneseeq Technology. The other authors declare no competing interests. Epub 2025/03/25. eng.
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https://christie.openrepository.com/handle/10541/628173
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