Early Detection Research Network

Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer.

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.

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

30033370

Cell, 2018, 174 (3)

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