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Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing
Open accessAbstract
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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“We and other groups have identified tumor alterations that reactivate AR signaling during treatment with an ARSI2,22–29.”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [25]
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“These mechanisms of resistance include AR gene amplification22,23, AR enhancer amplification2,24,25, AR mutation26, AR genomic structural rearrangements27, AR splice variants28 and polymorphisms in androgen metabolism genes29.”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [25]
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“…identified that a subset of the resistant mCRPC harbor AR genomic alterations through mutations, copy number gain, enhancer amplification, as well as increased resistant transcript variants (ARV7) ( Bubley and Balk, 2017 ; Henzler et al., 2016 ; Takeda et al., 2018 ; Viswanathan et al., 2018 ).”
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“Aside from gene amplification, AR protein overexpression in CRPC can be facilitated by tandem duplications of an enhancer element 650 kb upstream of the AR gene [112,113].”
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“tion [23,27], mutations that render AR less sensitive to ADT [28], AR gene rearrangements or splicing events that result in loss of functional LBD [9,27] (and thus, a constitutively active AR), or expression of the related NR glucocorticoid receptor that in a subset of cases can take over part of AR’s function in CaP…”
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Self-citationClinical implications of genomic alterations in metastatic prostate cancer
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“This is in addition to many known cancer drivers that alter CRE interactions, including the AR and FOXA1 enhancer amplifications in primary and metastatic prostate tumors (19, 20, 34, 36, 40, 78).”
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Self-citationThe role of cyclins in the development and progression of prostate cancer
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“Changes in transcriptional control mechanisms are associated with the progression of cancer and cancer stem cells, leading to treatment-resistance, recurrence and metastasis (88).”
BackgroundCDK4/6 Alters TBK1 Phosphorylation to Inhibit the STING Signaling Pathway in Prostate Cancer
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“These are markers characteristic of prostate cancer cells [23,30,31].”
BackgroundClinical Actionability of the Genomic Landscape of Metastatic Castration Resistant Prostate Cancer
Devlies, W., Eckstein, M., Cimadamore, A., Devos, G., Moris, L., den Broeck, T. V., Montironi, R., Joniau, S., Claessens, F., & Gevaert, T. (2020) · Cells · doi:10.3390/cells9112494 · Cited by 19
“In another study more than 70% of mCRPC patients had duplications of an upstream enhancer of AR, suggesting this to be a causative step in the development to CRPC [16].”
BackgroundSharifi, M. N., Sperger, J. M., Taylor, A. K., Tippins, K. E., Reese, S. R., Carreno, V., Kaufmann, K. R., Chang, A. H., Nunamaker, L. A., Linebarger, C., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-1509 · Cited by 26
Self-citationMolecular Pathology of Prostate Cancer
Kulaç, İ., Roudier, M. P., & Haffner, M. C. (2024) · Clinics in Laboratory Medicine · doi:10.1016/j.cll.2023.08.003 · Cited by 19
Intraindividual epigenetic heterogeneity underlying phenotypic subtypes of advanced prostate cancer
Mizuno, K., Ku, S., Venkadakrishnan, V. B., Bakht, M. K., Sigouros, M., Chan, J., Trigos, A., Driskill, J. H., Manohar, J., King, A. S., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-60654-z · Cited by 17
“However, the previously reported AR enhancer region 21 – 23 did not show signi fi cant correlations between DNA methylation and expression.”
Self-citationTan, K., Slevin, M. K., Leibowitz, M. L., Garrity-Janger, M., Shan, J., Li, H., & Meyerson, M. M. (2024) · Cell Genomics · doi:10.1016/j.xgen.2024.100588 · Cited by 18
Self-citationNordlund, J., Marincevic-Zuniga, Y., Cavelier, L. B., Raine, A., Martin, T., Lundmark, A., Abrahamsson, J., Norén‐Nyström, U., Lönnerholm, G., & Syvänen, A. (2020) · Scientific Reports · doi:10.1038/s41598-020-59214-w · Cited by 17
Morrison, G. J., Buckley, J. D., Ostrow, D. G., Varghese, B. A., Cen, S., Werbin, J. L., Ericson, N. G., Cunha, A. T., Lu, Y., George, T. C., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052571 · Cited by 17
Molecular Pathology of Prostate Cancer
Kulaç, İ., Roudier, M. P., & Haffner, M. C. (2021) · Surgical pathology clinics · doi:10.1016/j.path.2021.05.004 · Cited by 17
Genetic and Genomic Testing for Prostate Cancer: Beyond DNA Repair
Herberts, C., Wyatt, A. W., Nguyen, P. L., & Cheng, H. H. (2023) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_390384 · Cited by 15
Einstein, D. J., Arai, S., Calagua, C., Xie, F., Voznesensky, O. S., Capaldo, B. J., Luffman, C. I., Hecht, J. L., Balk, S. P., Sowalsky, A. G., et al. (2021) · JCO Precision Oncology · doi:10.1200/po.21.00059 · Cited by 16
Fan, H., Li, J., Manuel, A. M., & Zhao, Z. (2023) · Molecular Therapy - Nucleic Acids · doi:10.1016/j.omtn.2023.02.022 · Cited by 14
Overcoming oncogene addiction in breast and prostate cancers: a comparative mechanistic overview
Blatt, E. B., Kopplin, N. G., Kumar, S., Mu, P., Conzen, S. D., & Raj, G. V. (2020) · Endocrine Related Cancer · doi:10.1530/erc-20-0272 · Cited by 15
Christenson, M., Song, C. S., Liu, Y., & Chatterjee, B. (2022) · Cancers · doi:10.3390/cancers14040892 · Cited by 15
The epigenetic function of androgen receptor in prostate cancer progression
Sawada, T., Kanemoto, Y., Kurokawa, T., & Kato, S. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1083486 · Cited by 16
“For example, an increase in AR gene expression and mutations in cancer driver genes, such as PTEN, MYC, and TP53, are often observed in progressive CRPC (Takeda et al., 2018; Viswanathan et al., 2018).”
BackgroundChauhan, P. S., Alahi, I., Sinha, S. D., Ledet, E. M., Mueller, R., Linford, J., Shiang, A. L., Webster, J. B., Greiner, L. J., Yang, B., et al. (2024) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-24-1658 · Cited by 18
Zhu, X., Farsh, T., Vis, D. J., Yu, I. P. L., Li, H., Liu, T., Sjöström, M., Shrestha, R., Kneppers, J., Severson, T., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci178604 · Cited by 16
“Among the 45 pairs, L702H and H875Y were mechanisms typically originate in the PCa genome and manifest as amplifications of AR (4) and its upstream enhancer (5–7) and gain-of-function mutations in the ligand binding domain (8).”
BackgroundInfluentialPoluben, L., Nouri, M., Liang, J., Chen, S., Varkaris, A. S., Ersoy-Fazlioglu, B., Voznesensky, O. S., Lee, I. I., Qiu, X., Cato, L., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.115089 · Cited by 16
Self-citationDu, M., Huang, C., Tan, W. W., Kohli, M., & Wang, L. (2020) · Cancers · doi:10.3390/cancers12082139 · Cited by 15
“Recently, it was reported that a somatically acquired AR enhancer region, 650 kb upstream of AR, drives the progression of mCRPC [18,23,24].”
BackgroundResultMeltos: multi-sample tumor phylogeny reconstruction for structural variants
Ricketts, C., Seidman, D. N., Popic, V., Hormozdiari, F., Batzoglou, S., & Hajirasouliha, I. (2019) · Bioinformatics · doi:10.1093/bioinformatics/btz737 · Cited by 15
Emerging therapies to overcome antiandrogen resistance and beyond in lethal prostate cancer
Huang, F., Li, K., Shevach, J. W., & Wang, Q. (2025) · Journal of the National Cancer Center · doi:10.1016/j.jncc.2025.04.004 · Cited by 18
“62 A recent study that performed AR-targeted DNA sequencing using CRPC and patient-derived xenografts (PDX) tissues showed AR was amplified on extrachromosomal DNA (ecDNA), representing another mechanism that explains the increased AR gene copies and expression under AR-targeted therapies.”
Chen, H., Luo, J., Chen, S., Shi, B., Zheng, X., Ji, H., Zhang, X., Yin, Y., Du, K., Ding, J., et al. (2022) · Cell Death Discovery · doi:10.1038/s41420-022-00951-4 · Cited by 14
“It is noteworthy that copy number gain in the AR locus has been reported as one of the major mechanisms underlying ADT resistance in PCa, and that AR amplification occurs in the majority of CRPC and metastatic CRPC [34, 35].”
Zhou, T., & Feng, Q. F. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.924087 · Cited by 21
Genomic Characterization of Prostatic Basal Cell Carcinoma
Low, J., Ko, M., Hanratty, B. P., Patel, R. A., Bhamidipati, A., Heaphy, C. M., Sayar, E., Lee, J. K., Li, S., Marzo, A. M. D., et al. (2022) · American Journal Of Pathology · doi:10.1016/j.ajpath.2022.09.010 · Cited by 14
Self-citationThe yin and yang of chromosomal instability in prostate cancer
Carceles‐Cordon, M., Orme, J. J., Domenech, J. M. D., & Rodríguez-Bravo, V. (2024) · Nature Reviews Urology · doi:10.1038/s41585-023-00845-9 · Cited by 13
Akkermansia muciniphila Metabolite Inosine Inhibits Castration Resistance in Prostate Cancer
Yu, Y., Li, L., Yang, Q., Xue, J., Wang, B., Xie, M., Shangguan, W., Zhu, Z., & Wu, P. (2024) · Microorganisms · doi:10.3390/microorganisms12081653 · Cited by 16
Yang, Y., Badura, M. L., O’Leary, P. C., Delavan, H. M., Robinson, T. M., Egusa, E. A., Zhong, X., Swinderman, J. T., Li, H., Zhang, M., et al. (2024) · Nature Cancer · doi:10.1038/s43018-024-00848-4 · Cited by 19
Novel patterns of complex structural variation revealed across thousands of cancer genome graphsPreprint
Hadi, K., Yao, X., Behr, J. M., Deshpande, A. S., Xanthopoulakis, C., Rosiene, J. A., Darmofal, M., Tian, H., DeRose, J., Mortensen, R., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/836296 · Cited by 14
“, Lee, H., Darby, C. A. and Schatz, M. C. (2018). Piercing the dark matter: bioinformatics of long-range sequencing and mapping.”
Self-citationChi, K. N., McKay, R. R., Sandhu, S. K., Arranz, J. Á., Barthélémy, P., Hadaschik, B. A., Matsubara, N., Shore, N. D., Ye, D., Cascella, T., et al. (2025) · Future Oncology · doi:10.1080/14796694.2025.2502318 · Cited by 14
“AR LBD mutations are identified in up to 25% of cases [13]; however, in the majority of cases, ARPI resistance is associated with WT receptor over-expression [14,15].”
Patterns of intra- and intertumor phenotypic heterogeneity in lethal prostate cancer
Roudier, M. P., Gulati, R., Sayar, E., Patel, R. A., Tratt, M., Richards, H., Cejas, P., Gomez, M. M., Qiu, X., Xie, Y., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci186599 · Cited by 16
“%) evaluable patients (51, 52, 54).”
Self-citationPIP5K1α is Required for Promoting Tumor Progression in Castration-Resistant Prostate Cancer
Wang, T., Sarwar, M., Whitchurch, J. B., Collins, H. M., Green, T., Semenas, J., Ali, A., Roberts, C. J., Morris, R. D., Hubert, M., et al. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.798590 · Cited by 13
Molecular Underpinnings Governing Genetic Complexity of ETS-Fusion-Negative Prostate Cancer
Bhatia, V., & Ateeq, B. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.07.001 · Cited by 14
“Previously, CDK12 has been implicated in regulating the expression of several DDR genes [88,89], and was shown to be mutated in advanced CRPC patients [6,11,90].”
BackgroundZwaig, 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. (2022) · BMC Cancer · doi:10.1186/s12885-022-10359-z · Cited by 12
“Copy number changes were called using the TitanCNA 10x workflow [30], the ploidy was selected manually and plotting for the circos plots was done using the .”
MethodAndrogen receptor and estrogen receptor variants in prostate and breast cancers
López, J. C. V., Lange, C. A., & Dehm, S. M. (2024) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2024.106522 · Cited by 13
Self-citation
Metadata
- 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)
- 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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