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Cell DOI:10.1016/j.cell.2018.05.036

Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing.

Publication TypeJournal Article
Year of Publication2018
AuthorsViswanathan, SR, Ha, G, Hoff, AM, Wala, JA, Carrot-Zhang, J, Whelan, CW, Haradhvala, NJ, Freeman, SS, Reed, SC, Rhoades, J, Polak, P, Cipicchio, M, Wankowicz, SA, Wong, A, Kamath, T, Zhang, Z, Gydush, GJ, Rotem, D, J Love, C, Getz, G, Gabriel, S, Zhang, C-Z, Dehm, SM, Nelson, PS, Van Allen, EM, Choudhury, AD, Adalsteinsson, VA, Beroukhim, R, Taplin, M-E, Meyerson, M
Corporate AuthorsPCF/SU2C International Prostate Cancer Dream Team
JournalCell
Date Published2018 Jun 11
ISSN1097-4172
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.

DOI10.1016/j.cell.2018.05.036
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/29909985?dopt=Abstract

Alternate JournalCell
PubMed ID29909985
Grant ListR01 CA174777 / CA / NCI NIH HHS / United States
P50 CA097186 / CA / NCI NIH HHS / United States
K08 CA188615 / CA / NCI NIH HHS / United States
R01 CA215489 / CA / NCI NIH HHS / United States
R35 CA197568 / CA / NCI NIH HHS / United States