The mutational landscape of lethal castration-resistant prostate cancer
Open accessAbstract
Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains and losses, including ETS gene family fusions, PTEN loss and androgen receptor (AR) amplification, which drive prostate cancer development and progression to lethal, metastatic castration-resistant prostate cancer (CRPC). However, less is known about the role of mutations. Here we sequenced the exomes of 50 lethal, heavily pre-treated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment-naive, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPCs (2.00 per megabase) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1 that define a subtype of ETS gene family fusion-negative prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in approximately one-third of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Furthermore, we identified recurrent mutations in multiple chromatin- and histone-modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with the AR, which is required for AR-mediated signalling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signalling and increases tumour growth. Proteins that physically interact with the AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX (also known as KDM6A) and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signalling deregulated in prostate cancer, and prioritize candidates for future study.
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Tumor alterations that reactivate AR signaling during treatment with an ARSI have been identified.
“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 [23]
The paper reports aberrations in AR and interacting proteins in heavily pretreated castration-resistant prostate cancer and says androgen signaling can remain active after androgen-deprivation therapy (Abstract; page unavailable). It does not show that these alterations reactivate AR signaling during treatment with an AR signaling inhibitor (ARSI); its tested FOXA1 mutations instead repress androgen signaling. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMechanisms of ARSI resistance include AR gene amplification, AR enhancer amplification, AR mutation, AR genomic structural rearrangements, AR splice variants and polymorphisms in androgen metabolism genes.
“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 [23]
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- Authors
- Grasso, C. S., Wu, Y.-M., Robinson, D. R., Cao, X., Dhanasekaran, S. M., Khan, A. P., Quist, M. J., Jing, X., Lonigro, R. J., Brenner, J. C., Asangani, I. A., Ateeq, B., Chun, S. Y., Siddiqui, J., Sam, L., Anstett, M., Mehra, R., Prensner, J. R., Palanisamy, N., Ryslik, G. A., Vandin, F., Raphael, B. J., Kunju, L. P., Rhodes, D. R., Pienta, K. J., Chinnaiyan, A. M., & Tomlins, S. A.
- Affiliations
- University of Michigan (US)
- Howard Hughes Medical Institute (US)
- Yale University (US)
- Brown University (US)
- Corresponding author
- Pienta, Kenneth J.
- Chinnaiyan, Arul M.
- ORCID
- Grasso, Catherine S.
- Robinson, Dan R.
- Cao, Xuhong
- Dhanasekaran, Saravana M.
- Khan, Amjad P.
- Jing, Xiaojun
- Brenner, J. Chad
- Asangani, Irfan A.
- Ateeq, Bushra
- Siddiqui, Javed
- Mehra, Rohit
- Prensner, John R.
- Palanisamy, Nallasivam
- Ryslik, Gregory A.
- Vandin, Fabio
- Raphael, Benjamin J.
- Kunju, Lakshmi P.
- Rhodes, Daniel R.
- Pienta, Kenneth J.
- Chinnaiyan, Arul M.
- Tomlins, Scott A.
- Venue
- Nature
- Published
- 2012-05-20
- Volume
- 487
- Issue
- 7406
- Pages
- 239-243
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3396711
- OpenAlex
- W2051025382
- Cited by
- 2,517
- References
- 23
- Citations by year
- 2026: 75 · 2025: 128 · 2024: 136 · 2023: 181 · 2022: 178 · 2021: 199 · 2020: 233 · 2019: 193 · 2018: 205 · 2017: 195 · 2016: 194 · 2015: 212 · 2014: 177 · 2013: 169 · 2012: 33
- FWCI
- 152.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5r01ca013287-14)
- National Cancer Institute (P50-CA-69568, R01CA132874, U01CA111275, R01CA13287, P50CA069568, T32CA140044, P30CA046592, T32CA009676, U01CA113913)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › 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, somatic mutations, copy number alterations, chromatin modifiers, androgen receptor, FOXA1, KMT2D, TMPRSS2-ERG fusion, PTEN loss, androgen receptor amplification, chromosomal rearrangements
- MeSH terms
- Cells, Cultured, Humans, Male, Molecular Sequence Data, Mutation, Orchiectomy, Prostatic Neoplasms, Receptors, Androgen, Signal Transduction, Sequence Alignment, Cell Proliferation, Hepatocyte Nuclear Factor 3-alpha
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