The landscape of N<sup>6</sup>-methyladenosine in localized primary prostate cancer.
Abstract
N<sup>6</sup>-methyladenosine (m<sup>6</sup>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<sup>6</sup>A landscape of 162 localized prostate tumors with matched DNA, RNA and protein profiling. m<sup>6</sup>A abundance varied dramatically across tumors, with global patterns emerging via complex germline-somatic cooperative regulation. Individual germline polymorphisms regulated m<sup>6</sup>A abundance, cooperating with somatic mutation of cancer driver genes and m<sup>6</sup>A regulators. The resulting complex patterns were associated with prognostic clinical features and established the biomarker potential of global and locus-specific m<sup>6</sup>A patterns. Tumor hypoxia dysregulates m<sup>6</sup>A profiles, bridging prior genomic and proteomic observations. Specific m<sup>6</sup>A sites, such as those in VCAN, drive disease aggression, associating with poor outcomes, tumor growth and metastasis. m<sup>6</sup>A dysregulation is thus associated with key events in the natural history of prostate cancer: germline risk, microenvironmental dysregulation, somatic mutation and metastasis.
EDRN PI Authors
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Medline Author List
- Arbet J
- Bergeron A
- Berlin A
- Boutros PC
- Bristow RG
- Chen S
- Chen W
- Ci X
- Eng S
- Fleshner NE
- Fradet Y
- Gao T
- Guo WY
- He C
- He HH
- Houlahan KE
- Hovington H
- Hugh-White R
- Koritzinsky M
- Lacombe L
- Leong H
- Liu S
- Livingstone J
- Luo W
- Lupien M
- Orain M
- Pajdzik K
- Picard V
- Shao Y
- Sheng M
- Song Y
- Têtu B
- Wang M
- Wang S
- Wang Y
- Wei GH
- Wu X
- Xu K
- Xu W
- Xu X
- Xu X
- Zeltser N
- Zeng Y
- Zhu G
- Zhu H
- van der Kwast T