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The DNA methylation landscape of advanced prostate cancer.


ABSTRACT: Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome approaches. Notably, we observed that 22% of tumors exhibited a novel epigenomic subtype associated with hypermethylation and somatic mutations in TET2, DNMT3B, IDH1 and BRAF. We also identified intergenic regions where methylation is associated with RNA expression of the oncogenic driver genes AR, MYC and ERG. Finally, we showed that differential methylation during progression preferentially occurs at somatic mutational hotspots and putative regulatory regions. This study is a large integrated study of whole-genome, whole-methylome and whole-transcriptome sequencing in metastatic cancer that provides a comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer.

SUBMITTER: Zhao SG 

PROVIDER: S-EPMC7454228 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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The DNA methylation landscape of advanced prostate cancer.

Zhao Shuang G SG   Chen William S WS   Li Haolong H   Foye Adam A   Zhang Meng M   Sjöström Martin M   Aggarwal Rahul R   Playdle Denise D   Liao Arnold A   Alumkal Joshi J JJ   Das Rajdeep R   Chou Jonathan J   Hua Junjie T JT   Barnard Travis J TJ   Bailey Adina M AM   Chow Eric D ED   Perry Marc D MD   Dang Ha X HX   Yang Rendong R   Moussavi-Baygi Ruhollah R   Zhang Li L   Alshalalfa Mohammed M   Laura Chang S S   Houlahan Kathleen E KE   Shiah Yu-Jia YJ   Beer Tomasz M TM   Thomas George G   Chi Kim N KN   Gleave Martin M   Zoubeidi Amina A   Reiter Robert E RE   Rettig Matthew B MB   Witte Owen O   Yvonne Kim M M   Fong Lawrence L   Spratt Daniel E DE   Morgan Todd M TM   Bose Rohit R   Huang Franklin W FW   Li Hui H   Chesner Lisa L   Shenoy Tanushree T   Goodarzi Hani H   Asangani Irfan A IA   Sandhu Shahneen S   Lang Joshua M JM   Mahajan Nupam P NP   Lara Primo N PN   Evans Christopher P CP   Febbo Phillip P   Batzoglou Serafim S   Knudsen Karen E KE   He Housheng H HH   Huang Jiaoti J   Zwart Wilbert W   Costello Joseph F JF   Luo Jianhua J   Tomlins Scott A SA   Wyatt Alexander W AW   Dehm Scott M SM   Ashworth Alan A   Gilbert Luke A LA   Boutros Paul C PC   Farh Kyle K   Chinnaiyan Arul M AM   Maher Christopher A CA   Small Eric J EJ   Quigley David A DA   Feng Felix Y FY  

Nature genetics 20200713 8


Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome approaches. Notably, we observed that 22% of tumors exhibited a novel epigenomic subtype associat  ...[more]

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