Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing
Srinivas R Viswanathan, Gavin Ha, Andreas M Hoff, Jeremiah A Wala, Jian Carrot-Zhang, Christopher W Whelan, Nicholas J Haradhvala, Samuel S Freeman, Sarah C Reed, Justin Rhoades, Paz Polak, Michelle Cipicchio, Stephanie A Wankowicz, Alicia Wong, Tushar Kamath, Zhenwei Zhang, Gregory J Gydush, Denisse Rotem, PCF/SU2C International Prostate Cancer Dream Team, J Christopher Love, Gad Getz, Stacey Gabriel, Cheng-Zhong Zhang, Scott M Dehm, Peter S Nelson, Eliezer M Van Allen, Atish D Choudhury, Viktor A Adalsteinsson, Rameen Beroukhim, Mary-Ellen Taplin, Matthew Meyerson, Srinivas R Viswanathan, Gavin Ha, Andreas M Hoff, Jeremiah A Wala, Jian Carrot-Zhang, Christopher W Whelan, Nicholas J Haradhvala, Samuel S Freeman, Sarah C Reed, Justin Rhoades, Paz Polak, Michelle Cipicchio, Stephanie A Wankowicz, Alicia Wong, Tushar Kamath, Zhenwei Zhang, Gregory J Gydush, Denisse Rotem, PCF/SU2C International Prostate Cancer Dream Team, J Christopher Love, Gad Getz, Stacey Gabriel, Cheng-Zhong Zhang, Scott M Dehm, Peter S Nelson, Eliezer M Van Allen, Atish D Choudhury, Viktor A Adalsteinsson, Rameen Beroukhim, Mary-Ellen Taplin, Matthew Meyerson
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.
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.
Conflict of interest statement
Declaration of Interests
G.H., S.S.F., V.A.A.: Patent application WO2017161175A1 (ichorCNA)
C-Z.Z: Co-founder, advisor, and share-holder, Pillar Biosciences
E.M.V: Consultant, Tango Therapeutics, Genome Medical, Invitae; research funding, BMS and Novartis
A.D.C.: Receives research funding from Bayer
G.G.: Receives research funding from Bayer and IBM
M.M.: Scientific advisory board chair and equity holder, OrigiMed; research funding, Bayer; inventor of a patent for EGFR mutation diagnosis in lung cancer, licensed to LabCorp.
Copyright © 2018 Elsevier Inc. All rights reserved.
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Source: PubMed