Cited by 374Prostate Cancer Treatment and ResearchChromatin Remodeling and CancerCancer Genomics and Diagnostics

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

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Viswanathan, Srinivas R., Ha, Gavin, Hoff, Andreas M., Wala, Jeremiah A., Carrot-Zhang, Jian, Whelan, Christopher W., Haradhvala, Nicholas J., Freeman, Samuel S., Reed, Sarah C., Rhoades, Justin, Polak, Paz, Cipicchio, Michelle, Wankowicz, Stephanie A., Wong, Alicia, Kamath, Tushar, Zhang, Zhenwei, Gydush, Gregory J., Rotem, Denisse, Love, J. Christopher, Getz, Gad, Gabriel, Stacey, Zhang, Cheng-Zhong, Dehm, Scott M., Nelson, Peter S., Van Allen, Eliezer M., Choudhury, Atish D., Adalsteinsson, Viktor A., Beroukhim, Rameen, Taplin, Mary-Ellen, Meyerson, Matthew·2018·Cell

DOI 10.1016/j.cell.2018.05.036PMC PMC6046279

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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.

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Additional file 7 of Detection and genomic analysis of BRAF fusions in Juvenile Pilocytic Astrocytoma through the combination and integration of multi-omic data
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Additional file 3 of Detection and genomic analysis of BRAF fusions in Juvenile Pilocytic Astrocytoma through the combination and integration of multi-omic data
Zwaig, M., Baguette, A., Hu, B., Johnston, M. J. G., Lakkis, H., Nakada, E. M., Faury, D., Juretic, N., Ellezam, B., Weil, A. G., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22599047
Additional file 8 of Detection and genomic analysis of BRAF fusions in Juvenile Pilocytic Astrocytoma through the combination and integration of multi-omic data
Zwaig, M., Baguette, A., Hu, B., Johnston, M. J. G., Lakkis, H., Nakada, E. M., Faury, D., Juretic, N., Ellezam, B., Weil, A. G., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22599065
Additional file 5 of Detection and genomic analysis of BRAF fusions in Juvenile Pilocytic Astrocytoma through the combination and integration of multi-omic data
Zwaig, M., Baguette, A., Hu, B., Johnston, M. J. G., Lakkis, H., Nakada, E. M., Faury, D., Juretic, N., Ellezam, B., Weil, A. G., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22599056
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Additional file 6 of Detection and genomic analysis of BRAF fusions in Juvenile Pilocytic Astrocytoma through the combination and integration of multi-omic data
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Additional file 4 of Detection and genomic analysis of BRAF fusions in Juvenile Pilocytic Astrocytoma through the combination and integration of multi-omic data
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Additional file 2 of Detection and genomic analysis of BRAF fusions in Juvenile Pilocytic Astrocytoma through the combination and integration of multi-omic data
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Additional file 1 of Functional mapping of androgen receptor enhancer activity
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Additional file 2 of Functional mapping of androgen receptor enhancer activity
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Additional file 9 of Detection and genomic analysis of BRAF fusions in Juvenile Pilocytic Astrocytoma through the combination and integration of multi-omic data
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Additional file 4 of Functional mapping of androgen receptor enhancer activity
Huang, C.-C. F., Lingadahalli, S., Morova, T., Özturan, D., Hu, E., Yu, I. P. L., Linder, S., Hoogstraat, M., Stelloo, S., Sar, F., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14576606
Additional file 2 of Haplotype-resolved germline and somatic alterations in renal medullary carcinomas
Tan, K.-T., Kim, H., Carrot‐Zhang, J., Zhang, Y., Kim, W. J., Kugener, G., Wala, J. A., Howard, T. P., Chi, Y.-Y., Beroukhim, R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14985000
Self-citation
Additional file 1 of Dissecting transcription of the 8q24-MYC locus in prostate cancer recognizes the equilibration between androgen receptor direct and indirect dual-functions
Guo, J., Wei, Z., Jia, T., Wang, L., Nama, N., Liang, J., Liao, X., Liu, X., Gao, Y., Liu, X., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24303332
Additional file 10 of Detection and genomic analysis of BRAF fusions in Juvenile Pilocytic Astrocytoma through the combination and integration of multi-omic data
Zwaig, M., Baguette, A., Hu, B., Johnston, M. J. G., Lakkis, H., Nakada, E. M., Faury, D., Juretic, N., Ellezam, B., Weil, A. G., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22599074
Additional file 1 of Detection and genomic analysis of BRAF fusions in Juvenile Pilocytic Astrocytoma through the combination and integration of multi-omic data
Zwaig, M., Baguette, A., Hu, B., Johnston, M. J. G., Lakkis, H., Nakada, E. M., Faury, D., Juretic, N., Ellezam, B., Weil, A. G., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22599038
Additional file 1 of Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers
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Chromatin compaction upon CDK12 inhibition drives long gene silencing and a combinatorial lethal dependency on PAF1Preprint
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Aryl hydrocarbon receptor is critical for both AR-dependent and AR-indifferent enzalutamide resistance in castration-resistant prostate cancer
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A Pleiotropic Role of the SWI/SNF Complex in Cancer – Insights From Two Tumor Types : Small Cell Carcinoma of the Ovary, Hypercalcemic Type and Prostatic Carcinoma
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3D genome architecture and epigenetic regulation of lineage identity in advanced prostate cancer
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Molecular Oncologic Pathology of Solid and Soft Tissue Tumors
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Targeting CDKs in the RNAPII transcription cycle
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Androgen receptor drives divergent chromatin accessibility programs in benign and malignant prostate epithelial cells
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A novel multiplex digital PCR assay for simultaneous quantification of androgen receptor amplification, mutations, and splice variants in cell-free nucleic acids from metastatic castration-resistant prostate cancer
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“…nucleic acids (cfNAs) comprising both cell-free DNA (cfDNA) and cell-free RNA (cfRNA) offers a minimally invasive approach to capture the genomic and transcriptomic landscape of mCRPC, including spatial heterogeneity across metastatic sites and temporal evolution under treatment pressure [11,12].”
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Authors: Viswanathan, S. R., Ha, G., Hoff, A. M., Wala, J. A., Carrot-Zhang, J., Whelan, C. W., Haradhvala, N. J., Freeman, S. S., Reed, S. C., Rhoades, J., Polak, P., Cipicchio, M., Wankowicz, S. A., Wong, A., Kamath, T., Zhang, Z., Gydush, G. J., Rotem, D., Love, J. C., Getz, G., Gabriel, S., Zhang, C.-Z., Dehm, S. M., Nelson, P. S., Van Allen, E. M., Choudhury, A. D., Adalsteinsson, V. A., Beroukhim, R., Taplin, M.-E., & Meyerson, M.
Affiliations: Broad Institute (US)
Icahn School of Medicine at Mount Sinai (US)
Dana-Farber Cancer Institute (US)
University of Minnesota (US)
Fred Hutch Cancer Center (US)
Harvard University (US)
Corresponding author: Meyerson, Matthew
ORCID: Viswanathan, Srinivas R.
Ha, Gavin
Hoff, Andreas M.
Wala, Jeremiah A.
Whelan, Christopher W.
Haradhvala, Nicholas J.
Freeman, Samuel S.
Reed, Sarah C.
Rhoades, Justin
Polak, Paz
Cipicchio, Michelle
Wankowicz, Stephanie A.
Wong, Alicia
Kamath, Tushar
Zhang, Zhenwei
Rotem, Denisse
Love, J. Christopher
Getz, Gad
Gabriel, Stacey
Zhang, Cheng-Zhong
Dehm, Scott M.
Nelson, Peter S.
Choudhury, Atish D.
Adalsteinsson, Viktor A.
Beroukhim, Rameen
Taplin, Mary-Ellen
Meyerson, Matthew
Venue: Cell
Publisher: Elsevier BV
Published: 2018-07
Volume: 174
Issue: 2
Pages: 433-447.e19
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2018.05.036
PMC: PMC6046279
OpenAlex: W2807985734
Cited by: 365
References: 65
Citations by year: 2026: 17 · 2025: 28 · 2024: 47 · 2023: 48 · 2022: 59 · 2021: 51 · 2020: 53 · 2019: 45 · 2018: 16
FWCI: 31.27
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 376 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
Funders: Department of Defense (W81XWH-17-1-0358)
Prostate Cancer Foundation Young Investigator Award
Canadian Institutes of Health Research (MFE-140389)
Norwegian Cancer Society (PR-2007-0166)
NIH (K08 CA188615, R01CA174777, P01CA163227, NIH R01 CA215489)
NCI (R35 CA197568)
PCF-V Foundation
Movember
PCF
Gerstner Family Foundation
Prostate SPORE (P50CA097186)
Fund for Innovation in Cancer Informatics
American Cancer Society Research Professorship
American Association for Cancer Research (SU2C-AACR-DT0712)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: castration-resistant prostate cancer, metastatic prostate cancer, tandem duplication, genome rearrangement, cell-free DNA, linked-read sequencing
MeSH terms: Whole Genome Sequencing, Aged, Anilides, Enhancer Elements, Genetic, Haplotypes, Humans, Male, Middle Aged, Neoplasm Metastasis, Phenotype, Pyridines, Receptors, Androgen, Gene Rearrangement, Genes, myc, Prostate-Specific Antigen, Cyclin-Dependent Kinases, Gene Duplication, Protein Kinase Inhibitors, PTEN Phosphohydrolase, Genetic Loci, Prostatic Neoplasms, Castration-Resistant

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