Cell 2018 07 19;174(3):758-769.e9. Epub 2018 Jul 19.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA; Department of Radiation Oncology, UCSF, San Francisco, CA, USA; Department of Urology, UCSF, San Francisco, CA, USA. Electronic address:
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.