| Literature DB >> 29909985 |
Srinivas R Viswanathan1, Gavin Ha1, Andreas M Hoff2, Jeremiah A Wala1, Jian Carrot-Zhang1, Christopher W Whelan3, Nicholas J Haradhvala4, Samuel S Freeman5, Sarah C Reed6, Justin Rhoades6, Paz Polak7, Michelle Cipicchio6, Stephanie A Wankowicz8, Alicia Wong6, Tushar Kamath5, Zhenwei Zhang9, Gregory J Gydush6, Denisse Rotem6, J Christopher Love10, Gad Getz11, Stacey Gabriel6, Cheng-Zhong Zhang12, Scott M Dehm13, Peter S Nelson14, Eliezer M Van Allen8, Atish D Choudhury15, Viktor A Adalsteinsson10, Rameen Beroukhim16, Mary-Ellen Taplin15, Matthew Meyerson17.
Abstract
Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC), but there have been few whole-genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. Unexpectedly, these rearrangements include highly recurrent tandem duplications involving an upstream enhancer of AR in 70%-87% of cases compared with <2% of primary prostate cancers. A subset of cases displayed AR or MYC enhancer duplication in the context of a genome-wide tandem duplicator phenotype associated with CDK12 inactivation. Our findings highlight the complex genomic structure of mCRPC, nominate alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the non-coding mCRPC genome remain to be discovered.Entities:
Keywords: CDK12; MYC; androgen receptor; castration-resistant prostate cancer; cell-free DNA; enhancer; linked read whole-genome sequencing; non-coding cancer genome; structural variants; tandem duplicator phenotype
Mesh：
Substances：
Year: 2018 PMID： 29909985 PMCID： PMC6046279 DOI： 10.1016/j.cell.2018.05.036
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582