The landscape of N6-methyladenosine in localized primary prostate cancer

IF 31.7 1区生物学 Q1 GENETICS & HEREDITY

Nature genetics Pub Date : 2025-03-24 DOI:10.1038/s41588-025-02128-y

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

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引用次数: 0

Abstract

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.

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来源期刊

Nature genetics 生物-遗传学

CiteScore

43.00

自引率

2.60%

发文量

241

审稿时长

3 months

期刊介绍： Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human and plant traits and on other model organisms. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation. Integrative genetic topics comprise, but are not limited to: -Genes in the pathology of human disease -Molecular analysis of simple and complex genetic traits -Cancer genetics -Agricultural genomics -Developmental genetics -Regulatory variation in gene expression -Strategies and technologies for extracting function from genomic data -Pharmacological genomics -Genome evolution