The mutational landscape of lethal castration-resistant prostate cancer
- PMID: 22722839
- PMCID: PMC3396711
- DOI: 10.1038/nature11125
The mutational landscape of lethal castration-resistant prostate cancer
Abstract
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.
Conflict of interest statement
The University of Michigan has been issued a patent on the detection of ETS gene fusions in prostate cancer, on which S.A.T., R.M., D.R.R. and A.M.C. are listed as co-inventors. The University of Michigan licensed the diagnostic field of use to Gen-Probe, Inc. S.A.T. has served as a consultant to Compendia Biosciences and has received honoraria from Ventana/Roche. A.M.C. has served as a consultant for Gen-Probe, Inc. and Ventana/Roche. D.R.R. and A.M.C. are co-founders of Compendia Biosciences, which licensed Oncomine from the University of Michigan. M.A. is an employee of Compendia Biosciences. The remaining authors declare no conflicts of interest.
Figures
![Figure 1](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/3396711/bin/nihms368879f1.gif)
![Figure 2](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/3396711/bin/nihms368879f2.gif)
![Figure 3](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/3396711/bin/nihms368879f3.gif)
![Figure 4](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/3396711/bin/nihms368879f4.gif)
Comment in
-
Urological cancer: Genetic landscape studies of prostate cancer offer new clues.Nat Rev Clin Oncol. 2012 May 29;9(7):367. doi: 10.1038/nrclinonc.2012.94. Nat Rev Clin Oncol. 2012. PMID: 22641363 No abstract available.
-
Prostate cancer: Painting the genetic landscape of prostate cancer.Nat Rev Urol. 2012 Jun 12;9(7):352. doi: 10.1038/nrurol.2012.118. Nat Rev Urol. 2012. PMID: 22688960 No abstract available.
-
A picture with more details is painted for prostate cancer.Asian J Androl. 2012 Nov;14(6):799-800. doi: 10.1038/aja.2012.73. Epub 2012 Jul 30. Asian J Androl. 2012. PMID: 22842705 Free PMC article. No abstract available.
-
Mapping mutations in prostate cancer exomes.Asian J Androl. 2012 Nov;14(6):801-2. doi: 10.1038/aja.2012.75. Epub 2012 Jul 30. Asian J Androl. 2012. PMID: 22842706 Free PMC article.
-
Uncovering the genetic landscape driving castration-resistant prostate cancer.Cancer Biol Ther. 2013 May;14(5):399-400. doi: 10.4161/cbt.24426. Cancer Biol Ther. 2013. PMID: 23917376 Free PMC article.
Similar articles
-
Pioneer of prostate cancer: past, present and the future of FOXA1.Protein Cell. 2021 Jan;12(1):29-38. doi: 10.1007/s13238-020-00786-8. Epub 2020 Sep 18. Protein Cell. 2021. PMID: 32946061 Free PMC article. Review.
-
Uncovering the genetic landscape driving castration-resistant prostate cancer.Cancer Biol Ther. 2013 May;14(5):399-400. doi: 10.4161/cbt.24426. Cancer Biol Ther. 2013. PMID: 23917376 Free PMC article.
-
Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer.Nat Genet. 2012 May 20;44(6):685-9. doi: 10.1038/ng.2279. Nat Genet. 2012. PMID: 22610119 Free PMC article.
-
Androgen receptor (AR) aberrations in castration-resistant prostate cancer.Mol Cell Endocrinol. 2012 Sep 5;360(1-2):38-43. doi: 10.1016/j.mce.2011.12.019. Epub 2012 Jan 8. Mol Cell Endocrinol. 2012. PMID: 22245783 Review.
-
Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer.Cancer Res. 2009 Apr 1;69(7):2912-8. doi: 10.1158/0008-5472.CAN-08-3667. Cancer Res. 2009. PMID: 19339269
Cited by
-
Oncogenes and tumor suppressor genes: functions and roles in cancers.MedComm (2020). 2024 May 31;5(6):e582. doi: 10.1002/mco2.582. eCollection 2024 Jun. MedComm (2020). 2024. PMID: 38827026 Free PMC article. Review.
-
Additional Sex Combs-like Family Associated with Epigenetic Regulation.Int J Mol Sci. 2024 May 8;25(10):5119. doi: 10.3390/ijms25105119. Int J Mol Sci. 2024. PMID: 38791157 Free PMC article. Review.
-
Mixed Adenosquamous Cell Carcinoma of the Prostate with Paired Sequencing on the Primary and Liver Metastasis.Curr Oncol. 2024 Apr 24;31(5):2393-2399. doi: 10.3390/curroncol31050178. Curr Oncol. 2024. PMID: 38785459 Free PMC article.
-
PAX6 promotes neuroendocrine phenotypes of prostate cancer via enhancing MET/STAT5A-mediated chromatin accessibility.J Exp Clin Cancer Res. 2024 May 15;43(1):144. doi: 10.1186/s13046-024-03064-1. J Exp Clin Cancer Res. 2024. PMID: 38745318 Free PMC article.
-
Organoids derived from metastatic cancers: Present and future.Heliyon. 2024 Apr 27;10(9):e30457. doi: 10.1016/j.heliyon.2024.e30457. eCollection 2024 May 15. Heliyon. 2024. PMID: 38720734 Free PMC article. Review.
References
-
- Attard G, Reid AH, Olmos D, de Bono JS. Antitumouractivity with CYP17 blockade indicates that castration-resistant prostate cancer frequently remains hormone driven. Cancer Res. 2009;69:4937–4940. - PubMed
Publication types
MeSH terms
Substances
Associated data
- Actions
Grants and funding
- P30 CA046592/CA/NCI NIH HHS/United States
- P50 CA069568-14/CA/NCI NIH HHS/United States
- U01 CA113913-03/CA/NCI NIH HHS/United States
- T32 CA009676/CA/NCI NIH HHS/United States
- P50 CA69568/CA/NCI NIH HHS/United States
- P50 CA069568/CA/NCI NIH HHS/United States
- T32 CA140044/CA/NCI NIH HHS/United States
- R01 CA132874-05/CA/NCI NIH HHS/United States
- R01 CA132874/CA/NCI NIH HHS/United States
- U01 CA113913/CA/NCI NIH HHS/United States
- U01 CA111275-08/CA/NCI NIH HHS/United States
- R01CA13287/CA/NCI NIH HHS/United States
- U01 CA111275/CA/NCI NIH HHS/United States
- HHMI/Howard Hughes Medical Institute/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Research Materials
Miscellaneous