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Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer
Open accessAbstract
SUMMARY While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole genome and transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor / 38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kilobases upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.
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“Most PCas express AR throughout the course of the disease2–5”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [2]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The androgen receptor (AR) is a critical driver of prostate cancer (PCa).”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [2]
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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 [2]
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In the citing paper
“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 [2]
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In the citing paper
“However, deep deletions (primarily of BRCA2; Supplementary Fig. 23) occurred much more frequently in prostate cancer (33%) compared to other cancer types, consistent with previous observations28.”
From Pan-cancer landscape of homologous recombination deficiency. (2020) · cites this paper as [28]
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Metadata
- Authors
- Quigley, D. A., Dang, H. X., Zhao, S. G., Lloyd, P., Aggarwal, R., Alumkal, J. J., Foye, A., Kothari, V., Perry, M. D., Bailey, A. M., Playdle, D., Barnard, T. J., Zhang, L., Zhang, J., Youngren, J. F., Cieslik, M. P., Parolia, A., Beer, T. M., Thomas, G., Chi, K. N., Gleave, M., Lack, N. A., Zoubeidi, A., Reiter, R. E., Rettig, M. B., Witte, O., Ryan, C. J., Fong, L., Kim, W., Friedlander, T., Chou, J., Li, H., Das, R., Li, H., Moussavi-Baygi, R., Goodarzi, H., Gilbert, L. A., Lara, P. N., Evans, C. P., Goldstein, T. C., Stuart, J. M., Tomlins, S. A., Spratt, D. E., Cheetham, R. K., Cheng, D. T., Farh, K., Gehring, J. S., Hakenberg, J., Liao, A., Febbo, P. G., Shon, J., Sickler, B., Batzoglou, S., Knudsen, K. E., He, H. H., Huang, J., Wyatt, A. W., Dehm, S. M., Ashworth, A., Chinnaiyan, A. M., Maher, C. A., Small, E. J., & Feng, F. Y.
- Affiliations
- University of California, San Francisco (US)
- Washington University in St. Louis (US)
- University of Michigan (US)
- Oregon Health & Science University (US)
- BC Cancer Agency (CA)
- University of British Columbia (CA)
- University of California, Los Angeles (US)
- University of Minnesota (US)
- University of California Davis Medical Center (US)
- University of California, Santa Cruz (US)
- Illumina (United States) (US)
- Thomas Jefferson University (US)
- University Health Network (CA)
- Duke University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Chinnaiyan, Arul M.
- Maher, Christopher A.
- Small, Eric J.
- Feng, Felix Y.
- ORCID
- Quigley, David A.
- Dang, Ha X.
- Zhao, Shuang G.
- Lloyd, Paul
- Aggarwal, Rahul
- Alumkal, Joshi J.
- Foye, Adam
- Kothari, Vishal
- Perry, Marc D.
- Zhang, Li
- Zhang, Jin
- Youngren, Jack F.
- Cieslik, Marcin P.
- Parolia, Abhijit
- Beer, Tomasz M.
- Thomas, George
- Chi, Kim N.
- Gleave, Martin
- Lack, Nathan A.
- Zoubeidi, Amina
- Reiter, Robert E.
- Rettig, Matthew B.
- Witte, Owen
- Ryan, Charles J.
- Fong, Lawrence
- Kim, Won
- Friedlander, Terence
- Chou, Jonathan
- Li, Haolong
- Das, Rajdeep
- Li, Hui
- Goodarzi, Hani
- Gilbert, Luke A.
- Lara, Primo N.
- Evans, Christopher P.
- Goldstein, Theodore C.
- Stuart, Joshua M.
- Tomlins, Scott A.
- Spratt, Daniel E.
- Farh, Kyle
- Gehring, Julian S.
- Hakenberg, Jörg
- Shon, John
- Sickler, Brad
- Batzoglou, Serafim
- Knudsen, Karen E.
- He, Housheng H.
- Huang, Jiaoti
- Wyatt, Alexander W.
- Dehm, Scott M.
- Ashworth, Alan
- Chinnaiyan, Arul M.
- Maher, Christopher A.
- Small, Eric J.
- Feng, Felix Y.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 174
- Issue
- 3
- Pages
- 758-769.e9
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6425931
- OpenAlex
- W2884001931
- Semantic Scholar
- c72ffe522bd85597687b47e4d3db90ec72b4fc80
- Cited by
- 733
- References
- 73
- Citations by year
- 2026: 48 · 2025: 73 · 2024: 102 · 2023: 107 · 2022: 94 · 2021: 110 · 2020: 102 · 2019: 81 · 2018: 15
- FWCI
- 58.02
- Type
- journal article
- Language
- en
- Update notices
- erratum (2018-10-18)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Stand Up To Cancer-Prostate Cancer Foundation Prostate Cancer Dream Team Award (SU2C-AACR-DT0812, SU2C-AACR-DT0712)
- Movember Foundation
- Goldberg-Benioff Research Fund for Prostate Cancer Translational Biology
- Prostate Cancer Foundation Challenge
- V Foundation
- BRCA Foundation Young Investigator Award
- Department of Defense (W81XWH-16-1-0747, W81XWH-15-1-0562, PC160429, W81XWH-17-1-0192)
- Early Detection Research Network (U01 CA214170)
- Prostate SPORE (P50 CA186786, P50 CA097186)
- NIH (R01CA174777)
- NCI T32 (CA108462)
- Prostate Cancer Foundation Young Investigator Awards
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- castration-resistant prostate cancer, metastatic prostate cancer, structural variants, androgen receptor, c-Myc, tandem duplication, long non-coding RNA, DNA repair deficiency, CDK12, TP53, chromothripsis, BRCA2
- MeSH terms
- Whole Genome Sequencing, Aged, Aged, 80 and over, Humans, Male, Middle Aged, Mutation, Neoplasm Metastasis, Prostatic Neoplasms, Receptors, Androgen, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-myc, Cyclin-Dependent Kinases, Tandem Repeat Sequences, Gene Expression Profiling, Genomics, BRCA2 Protein, Genomic Structural Variation, DNA Copy Number Variations, Exome
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