You are here

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
Date Published2018 07 12
KeywordsAged, Anilides, Cyclin-Dependent Kinases, Enhancer Elements, Genetic, Gene Duplication, Gene Rearrangement, Genes, myc, Genetic Loci, Haplotypes, Humans, Male, Middle Aged, Neoplasm Metastasis, Phenotype, Prostate-Specific Antigen, Prostatic Neoplasms, Castration-Resistant, Protein Kinase Inhibitors, PTEN Phosphohydrolase, Pyridines, Receptors, Androgen, Whole Genome Sequencing

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.


Alternate JournalCell
PubMed ID29909985
PubMed Central IDPMC6046279
Grant ListR01 CA188228 / CA / NCI NIH HHS / United States
P50 CA090381 / CA / NCI NIH HHS / United States
MFE-140389 / / CIHR / Canada
R01 CA174777 / CA / NCI NIH HHS / United States
P50 CA097186 / CA / NCI NIH HHS / United States
K08 CA188615 / CA / NCI NIH HHS / United States
T32 HG002295 / HG / NHGRI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
R01 CA215489 / CA / NCI NIH HHS / United States
R35 CA197568 / CA / NCI NIH HHS / United States
P01 CA163227 / CA / NCI NIH HHS / United States