Journal
Nature Genetics
Authors
Shuang G Zhao, William S Chen, Haolong Li, Adam Foye, Meng Zhang, Martin Sjöström, Rahul Aggarwal, Denise Playdle, Arnold Liao, Joshi J Alumkal, Rajdeep Das, Jonathan Chou, Junjie T Hua, Travis J Barnard, Adina M Bailey, Eric D Chow, Marc D Perry, Ha X Dang, Rendong Yang, Ruhollah Moussavi-Baygi, Li Zhang, Mohammed Alshalalfa, S Laura Chang, Kathleen E Houlahan, Yu-Jia Shiah, Tomasz M Beer, George Thomas, Kim N Chi, Martin Gleave, Amina Zoubeidi, Robert E Reiter, Matthew B Rettig, Owen Witte, M Yvonne Kim, Lawrence Fong, Daniel E Spratt, Todd M Morgan, Rohit Bose, Franklin W Huang, Hui Li, Lisa Chesner, Tanushree Shenoy, Hani Goodarzi, Irfan A Asangani, Shahneen Sandhu, Joshua M Lang, Nupam P Mahajan, Primo N Lara, Christopher P Evans, Phillip Febbo, Serafim Batzoglou, Karen E Knudsen, Housheng H He, Jiaoti Huang, Wilbert Zwart, Joseph F Costello, Jianhua Luo, Scott A Tomlins, Alexander W Wyatt, Scott M Dehm, Alan Ashworth, Luke A Gilbert, Paul C Boutros, Kyle Farh, Arul M Chinnaiyan, Christopher A Maher, Eric J Small, David A Quigley, Felix Y Feng

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.

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