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Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer.


ABSTRACT: 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.

SUBMITTER: Quigley DA 

PROVIDER: S-EPMC6425931 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer.

Quigley David A DA   Dang Ha X HX   Zhao Shuang G SG   Lloyd Paul P   Aggarwal Rahul R   Alumkal Joshi J JJ   Foye Adam A   Kothari Vishal V   Perry Marc D MD   Bailey Adina M AM   Playdle Denise D   Barnard Travis J TJ   Zhang Li L   Zhang Jin J   Youngren Jack F JF   Cieslik Marcin P MP   Parolia Abhijit A   Beer Tomasz M TM   Thomas George G   Chi Kim N KN   Gleave Martin M   Lack Nathan A NA   Zoubeidi Amina A   Reiter Robert E RE   Rettig Matthew B MB   Witte Owen O   Ryan Charles J CJ   Fong Lawrence L   Kim Won W   Friedlander Terence T   Chou Jonathan J   Li Haolong H   Das Rajdeep R   Li Hui H   Moussavi-Baygi Ruhollah R   Goodarzi Hani H   Gilbert Luke A LA   Lara Primo N PN   Evans Christopher P CP   Goldstein Theodore C TC   Stuart Joshua M JM   Tomlins Scott A SA   Spratt Daniel E DE   Cheetham R Keira RK   Cheng Donavan T DT   Farh Kyle K   Gehring Julian S JS   Hakenberg Jörg J   Liao Arnold A   Febbo Philip G PG   Shon John J   Sickler Brad B   Batzoglou Serafim S   Knudsen Karen E KE   He Housheng H HH   Huang Jiaoti J   Wyatt Alexander W AW   Dehm Scott M SM   Ashworth Alan A   Chinnaiyan Arul M AM   Maher Christopher A CA   Small Eric J EJ   Feng Felix Y FY  

Cell 20180719 3


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 e  ...[more]

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