The DNA methylation landscape of advanced prostate cancer.

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.

Aggarwal R, Alshalalfa M, Alumkal JJ, Asangani IA, Ashworth A, Bailey AM, Barnard TJ, Batzoglou S, Beer TM, Bose R, Boutros PC, Chen WS, Chesner L, Chi KN, Chinnaiyan AM, Chou J, Chow ED, Costello JF, Dang HX, Das R, Dehm SM, Evans CP, Farh K, Febbo P, Feng FY, Fong L, Foye A, Gilbert LA, Gleave M, Goodarzi H, He HH, Houlahan KE, Hua JT, Huang FW, Huang J, Knudsen KE, Lang JM, Lara PN, Laura Chang S, Li H, Li H, Liao A, Luo J, Mahajan NP, Maher CA, Morgan TM, Moussavi-Baygi R, Perry MD, Playdle D, Quigley DA, Reiter RE, Rettig MB, Sandhu S, Shenoy T, Shiah YJ, Sjöström M, Small EJ, Spratt DE, Thomas G, Tomlins SA, Witte O, Wyatt AW, Yang R, Yvonne Kim M, Zhang L, Zhang M, Zhao SG, Zoubeidi A, Zwart W


Nat. Genet., 2020

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