TY - JOUR
T1 - Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing
AU - PCF/SU2C International Prostate Cancer Dream Team
AU - Viswanathan, Srinivas R.
AU - Ha, Gavin
AU - Hoff, Andreas M.
AU - Wala, Jeremiah A.
AU - Carrot-Zhang, Jian
AU - Whelan, Christopher W.
AU - Haradhvala, Nicholas J.
AU - Freeman, Samuel S.
AU - Reed, Sarah C.
AU - Rhoades, Justin
AU - Polak, Paz
AU - Cipicchio, Michelle
AU - Wankowicz, Stephanie A.
AU - Wong, Alicia
AU - Kamath, Tushar
AU - Zhang, Zhenwei
AU - Gydush, Gregory J.
AU - Rotem, Denisse
AU - Love, J. Christopher
AU - Getz, Gad
AU - Gabriel, Stacey
AU - Zhang, Cheng Zhong
AU - Dehm, Scott M.
AU - Nelson, Peter S.
AU - Van Allen, Eliezer M.
AU - Choudhury, Atish D.
AU - Adalsteinsson, Viktor A.
AU - Beroukhim, Rameen
AU - Taplin, Mary Ellen
AU - Meyerson, Matthew
N1 - Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/7/12
Y1 - 2018/7/12
N2 - 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. Linked-read genome sequencing data from patients highlight that amplification of an enhancer upstream of the androgen receptor locus is a key feature of metastatic castration-resistant prostate cancer.
AB - 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. Linked-read genome sequencing data from patients highlight that amplification of an enhancer upstream of the androgen receptor locus is a key feature of metastatic castration-resistant prostate cancer.
KW - CDK12
KW - MYC
KW - androgen receptor
KW - castration-resistant prostate cancer
KW - cell-free DNA
KW - enhancer
KW - linked read whole-genome sequencing
KW - non-coding cancer genome
KW - structural variants
KW - tandem duplicator phenotype
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U2 - 10.1016/j.cell.2018.05.036
DO - 10.1016/j.cell.2018.05.036
M3 - Article
C2 - 29909985
AN - SCOPUS:85048296339
SN - 0092-8674
VL - 174
SP - 433-447.e19
JO - Cell
JF - Cell
IS - 2
ER -
