N6-methyladenosine (m6A), 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 m6A landscape of 162 localized prostate tumors with matched DNA, RNA and protein profiling. m6A abundance varied dramatically across tumors, with global patterns emerging via complex germline-somatic cooperative regulation. Individual germline polymorphisms regulated m6A abundance, cooperating with somatic mutation of cancer driver genes and m6A regulators. The resulting complex patterns were associated with prognostic clinical features and established the biomarker potential of global and locus-specific m6A patterns. Tumor hypoxia dysregulates m6A profiles, bridging prior genomic and proteomic observations. Specific m6A sites, such as those in VCAN, drive disease aggression, associating with poor outcomes, tumor growth and metastasis. m6A dysregulation is thus associated with key events in the natural history of prostate cancer: germline risk, microenvironmental dysregulation, somatic mutation and metastasis.
Nature genetics. 2025 Mar 24 [Epub ahead of print]
Xin Xu, Helen Zhu, Rupert Hugh-White, Julie Livingstone, Stefan Eng, Nicole Zeltser, Yujuan Wang, Kinga Pajdzik, Sujun Chen, Kathleen E Houlahan, Wenqin Luo, Shun Liu, Xi Xu, Minzhi Sheng, Wang Yuan Guo, Jaron Arbet, Yuxi Song, Miranda Wang, Yong Zeng, Shiyan Wang, Guanghui Zhu, Tingxiao Gao, Wei Chen, Xinpei Ci, Wenjie Xu, Kexin Xu, Michele Orain, Valerie Picard, Helene Hovington, Alain Bergeron, Louis Lacombe, Bernard Têtu, Yves Fradet, Mathieu Lupien, Gong-Hong Wei, Marianne Koritzinsky, Robert G Bristow, Neil E Fleshner, Xue Wu, Yang Shao, Chuan He, Alejandro Berlin, Theodorus van der Kwast, Hon Leong, Paul C Boutros, Housheng Hansen He
Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada., Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA., Department of Chemistry, the University of Chicago, Chicago, IL, USA., Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada., 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., Division of Cancer Sciences, University of Manchester, Manchester, UK., Geneseeq Research Institute, Geneseeq Technology lnc., Toronto, Ontario, Canada., Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. ., Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. .