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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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BackgroundUtility of ctDNA to support patient selection for early phase clinical trials: the TARGET study
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Self-citationTumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer
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BackgroundSelf-citationResolving the full spectrum of human genome variation using Linked-ReadsPreprint
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Towards precision oncology in advanced prostate cancer
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“This study and others (25, 34, 36, 37) support continued evolution of AR gene alterations during disease progression.”
ResultDeep whole-genome ctDNA chronology of treatment-resistant prostate cancer
Herberts, C., Annala, M., Sipola, J., Ng, S. W. S., Chen, X. E., Nurminen, A., Korhonen, O. V., Munzur, A. D., Beja, K., Schönlau, E., et al. (2022) · Nature · doi:10.1038/s41586-022-04975-9 · Cited by 193
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Self-citationProspective Comprehensive Genomic Profiling of Primary and Metastatic Prostate Tumors
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“CDK12 is a candidate biomarker for PARP inhibition(4) on the basis of preclinical studies(19,20); however, gLOH-H was significantly less frequent for CDK12-altered cases; this finding is consistent with recent studies suggesting that CDK12 GAs are associated with a focal tandem duplication phenotype that is distinct f…”
ResultThe main sources of circulating cell-free DNA: Apoptosis, necrosis and active secretion
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Self-citationAndrogen receptor (AR) heterogeneity in prostate cancer and therapy resistance
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Self-citationNSD2 is a conserved driver of metastatic prostate cancer progression
Aytés, À., Giacobbe, A., Mitrofanova, A., Ruggero, K., Cyrta, J., Arriaga, J. M., Palomero, L., Farran-Matas, S., Rubin, M. A., Shen, M. M., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07511-4 · Cited by 122
CDK12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS1‐ErbB‐PI3K signaling
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CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation
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“CDK12-Bi inactivation in prostate cancer was associated with a higher prevalence of small-fragment copy-number alterations and a higher number of breakpoints across the genome, consistent with the previously described tandem duplicator phenotype [9,25], as tandem duplications are difficult to characterize directly usi…”
BackgroundA new era of long-read sequencing for cancer genomics
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“For example, the AR is often activated by amplifications of its enhancer that do not include the gene itself 146,156 .”
BackgroundSelf-citationZhu, Y., Dalrymple, S. L., Coleman, I. M., Zheng, S. L., Xu, J., Hooper, J. E., Antonarakis, E. S., Marzo, A. M. D., Meeker, A. K., Nelson, P. S., et al. (2020) · Oncogene · doi:10.1038/s41388-020-01479-6 · Cited by 107
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“An enhancer region 640 kb upstream ofARwas recently reported to contribute to increased AR expression through focal tandem duplications in patients with mCRPC (32, 33).”
BackgroundSelf-citationvan Belzen, I. A. E. M., Schönhuth, A., Kemmeren, P., & Hehir‐Kwa, J. Y. (2021) · npj Precision Oncology · doi:10.1038/s41698-021-00155-6 · Cited by 102
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“%) had evidence of focal TD.”
BackgroundMethodInfluentialSelf-citationDarolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models
Sugawara, T., Baumgart, S. J., Nevedomskaya, E., Reichert, K., Steuber, H., Lejeune, P., Mumberg, D., & Haendler, B. (2019) · International Journal of Cancer · doi:10.1002/ijc.32242 · Cited by 95
“For the AR N/C interaction assay, HCT-116 cells were seeded into 6-well plates and transfected 1 day later with 2 μg of pFR-Luc reporter vector, and 250 ng of pCMV-AD-AR (2-554) and pCMV-BD-AR(665-918) plasmids.”
MethodA noncanonical AR addiction drives enzalutamide resistance in prostate cancer
He, Y., Wei, T., Ye, Z., Orme, J. J., Lin, D., Sheng, H., Fazli, L., Karnes, R. J., Jiménez, R. E., Wang, L., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-21860-7 · Cited by 94
Illuminating the noncoding genome in cancer
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Self-citationCDK12 phosphorylates 4E-BP1 to enable mTORC1-dependent translation and mitotic genome stabilityPreprint
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Targeting DNA Damage Response in Prostate and Breast Cancer
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“been described for an enhancer of the AR potentially responsible for disease progression on androgen pathway inhibitors [44,45].”
BackgroundAggarwal, R. R., Quigley, D. A., Huang, J., Zhang, L., Beer, T. M., Rettig, M. B., Reiter, R. E., Gleave, M. E., THOMAS, G. V., Foye, A., et al. (2019) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-18-1101 · Cited by 80
Malihi, P. D., Graf, R. P., Rodríguez, Á., Ramesh, N., Lee, J. S. H., Sutton, R., Jiles, R., Velasco, C. R., Sei, E., Kolatkar, A. R., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-4100 · Cited by 78
“A probable explanation for some of the AR-expressing mCRPC cases with no or low-level AR amplification may have been the presence of amplification in the enhancer region upstream of AR (5, 6).”
BackgroundCDK12: A Potent Target and Biomarker for Human Cancer Therapy
Liang, S., Hu, L., Wu, Z., Chen, Z., Liu, S., Xu, X., & Qian, A. (2020) · Cells · doi:10.3390/cells9061483 · Cited by 76
“Recent studies also show that inactivation of CDK12 (biallelic inactivation) is associated with a global tandem duplication phenotype [72,73].”
BackgroundSokol, E. S., Pavlick, D. C., Frampton, G. M., Ross, J. S., Miller, V. A., Ali, S. M., Lotan, T. L., Pardoll, D. M., Chung, J., & Antonarakis, E. S. (2019) · The Oncologist · doi:10.1634/theoncologist.2019-0214 · Cited by 74
“In ovarian and prostate cancers, CDK12 loss-of-function (CDK12-LOF) alterations are not associated with a homologous recombination deficiency (HRD) phenotype but are instead associated with the tandem-duplicator phenotype (TDP), a genomic signature characterized by focal tandem duplications (FTDs) with a bimodal size…”
BackgroundMethodResultInfluentialAndrogen receptor and MYC equilibration centralizes on developmental super-enhancer
Guo, H., Wu, Y., Nouri, M., Spisák, S., Russo, J. W., Sowalsky, A. G., Pomerantz, M. M., Wei, Z., Korthauer, K. D., Seo, J.-H., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27077-y · Cited by 77
Accelerating precision medicine in metastatic prostate cancer
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“, 2015) or its enhancer (Takeda et al., 2018; Viswanathan et al., 2018) are frequently observed in metastatic castration-resistant prostate cancer (mCRPC).”
BackgroundSelf-citationThe role of the histone H3 variant CENPA in prostate cancer
Saha, A. K., Contreras-Galindo, R., Niknafs, Y. S., Iyer, M. K., Qin, T., Padmanabhan, K., Siddiqui, J., Palande, M., Wang, C., Qian, B., et al. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.010080 · Cited by 70
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Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer
Zhou, S., Hawley, J. R., Soares, F., Grillo, G., Teng, M., Tonekaboni, S. A. M., Hua, J. T., Kron, K. J., Mazrooei, P., Ahmed, M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-14318-9 · Cited by 69
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Oncogenic CDK13 mutations impede nuclear RNA surveillance
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“deletions for PTEN because of normal cell contamination, and may not detect certain structural alterations detectable through linked‐ read genome sequencing.(31)”
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“However, all patients will ultimately relapse with incurable castration‐ resistant prostate cancer (CRPC).(1) Previous studies demonstrated that lipid metabolism was altered during the development of CRPC, and an increase in intratumoral essential polyunsaturated fatty acids (PUFAs) was observed.”
BackgroundInsight into Recent Advances in Degrading Androgen Receptor for Castration-Resistant Prostate Cancer
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A Practical Guide for Structural Variation Detection in the Human Genome
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“For example, linked-read sequencing was used to resolve haplotypes and somatic SVs in metastatic castration-resistant prostate cancers (Viswanathan et al., 2018).”
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Androgen receptor-binding sites are highly mutated in prostate cancer
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Aneuploidy and complex genomic rearrangements in cancer evolution
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“Chromoplexy chains often co-occur with other rearrangement patterns, such as chromothripsis (discussed below) and may have a causal role in some of these events 114,117,134,135 .”
The landscape of RNA polymerase II–associated chromatin interactions in prostate cancer
Ramanand, S. G., Chen, Y., Yuan, J., Daescu, K., Lambros, M. B. K., Houlahan, K. E., Carreira, S., Yuan, W., Baek, G., Sharp, A., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci134260 · Cited by 54
Genomic Profiling of Prostate Cancer: An Updated Review
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Clinical Applications of Liquid Biopsy in Prostate Cancer: From Screening to Predictive Biomarker
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Androgen Receptor-Mediated Transcription in Prostate Cancer
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New Prognostic Biomarkers in Metastatic Castration-Resistant Prostate Cancer
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“Its alterations are found in nearly 10% of mCRPC patients [6,60], but its loss does not determine the same mutational signature as BRCA1 or BRCA2 biallelic loss [74,75].”
BackgroundFuture directions for precision oncology in prostate cancer
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“In CRPC, amplification of an upstream enhancer of the androgen receptor (AR) gene leads to resistance to AR pathway inhibitor (ARPI) therapy.(4,15,16) A comprehensive analysis of nearly 200 patients with metastatic CRPC defined distinct genomic subgroups by WGS, including a cluster with a”
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Structural variants shape driver combinations and outcomes in pediatric high-grade glioma
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“A plateau of amplification and 5hmC/hypomethylation of both the AR gene itself and its regulatory plexus of coampli-fied enhancers, is thought to be a critical driver of overexpression and resistance to therapies targeting AR 4,5,7,11,12 .”
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“In 2018, Viswanathan et al. performed a linked-read whole-genome sequencing of 23 metastatic castration-resistant prostate cancers using biopsy specimens [50].”
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Self-citationCDK12: cellular functions and therapeutic potential of versatile player in cancer
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“The CDK12-specific focal tandem duplications with a high number of duplications and fusions can lead to the differential expression of oncogenic drivers such as CCND1 or AR (androgen receptor) or c-MYC enhancers as a secondary genetic event of CDK12 inactivation (88,89,111).”
BackgroundRecent Discoveries in the Androgen Receptor Pathway in Castration-Resistant Prostate Cancer
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“Amplifications of the AR and its enhancer are associated with higher levels of AR expression, and over-expressing the AR in prostate cancer cell lines causes enzalutamide-resistance (20, 21).”
BackgroundDNA repair defects in prostate cancer: impact for screening, prognostication and treatment
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Darolutamide antagonizes androgen signaling by blocking enhancer and super‐enhancer activation
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“Indeed, a majority of metastatic PCa lesions have amplification of the AR gene and/or of an upstream regulatory enhancer element (Quigley et al., 2018; Robinson et al., 2011; Takeda et al., 2018; Viswanathan et al., 2018).”
BackgroundThe genetic evolution of acral melanoma
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“Tumor purity and ploidy were resolved by using the following formula 49 : Here ρ and φ represent tumorpurity and ploidy, respectively.”
Larsson, P., Khaja, A. S. S., Semenas, J., Wang, T., Sarwar, M., Dizeyi, N., Simoulis, A., Hedblom, A., Wai, S. N., Ødum, N., et al. (2019) · International Journal of Cancer · doi:10.1002/ijc.32607 · Cited by 39
“recently reported to be associated with inactivated tumor suppressor PTEN, a negative regulator of PI3K/AKT pathways.(3,4)”
Background
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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