Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer.

Published

Journal Article

While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.

Full Text

Duke Authors

Cited Authors

  • Quigley, DA; Dang, HX; Zhao, SG; Lloyd, P; Aggarwal, R; Alumkal, JJ; Foye, A; Kothari, V; Perry, MD; Bailey, AM; Playdle, D; Barnard, TJ; Zhang, L; Zhang, J; Youngren, JF; Cieslik, MP; Parolia, A; Beer, TM; Thomas, G; Chi, KN; Gleave, M; Lack, NA; Zoubeidi, A; Reiter, RE; Rettig, MB; Witte, O; Ryan, CJ; Fong, L; Kim, W; Friedlander, T; Chou, J; Li, H; Das, R; Li, H; Moussavi-Baygi, R; Goodarzi, H; Gilbert, LA; Lara, PN; Evans, CP; Goldstein, TC; Stuart, JM; Tomlins, SA; Spratt, DE; Cheetham, RK; Cheng, DT; Farh, K; Gehring, JS; Hakenberg, J; Liao, A; Febbo, PG; Shon, J; Sickler, B; Batzoglou, S; Knudsen, KE; He, HH; Huang, J; Wyatt, AW; Dehm, SM; Ashworth, A; Chinnaiyan, AM; Maher, CA; Small, EJ; Feng, FY

Published Date

  • July 26, 2018

Published In

Volume / Issue

  • 174 / 3

Start / End Page

  • 758 - 769.e9

PubMed ID

  • 30033370

Pubmed Central ID

  • 30033370

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2018.06.039

Language

  • eng

Conference Location

  • United States