The DNA methylation landscape of advanced prostate cancer.

Journal Article (Journal Article;Multicenter Study)

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.

Full Text

Duke Authors

Cited Authors

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

Published Date

  • August 2020

Published In

Volume / Issue

  • 52 / 8

Start / End Page

  • 778 - 789

PubMed ID

  • 32661416

Pubmed Central ID

  • PMC7454228

Electronic International Standard Serial Number (EISSN)

  • 1546-1718

Digital Object Identifier (DOI)

  • 10.1038/s41588-020-0648-8

Language

  • eng

Conference Location

  • United States