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The mutational landscape of lethal castration-resistant prostate cancer

Nature volume 487, pages 239–243 (2012)Cite this article

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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)1. However, less is known about the role of mutations2,3,4. 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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Figure 1: Integrated mutational landscape of lethal metastatic CRPC.
Figure 2: Integrated exome sequencing and copy number analysis highlights novel aspects of ETS genes in prostate cancer biology: deregulation of CHD1 and ETS2.
Figure 3: CRPC harbours mutational aberrations in chromatin/histone modifiers that physically interact with the AR.
Figure 4: Recurrent mutations in the AR collaborating factor FOXA1 promote tumour growth and affect AR signalling.

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Gene Expression Omnibus

Data deposits

Copy number and gene expression data are available from the Gene Expression Omnibus under accession GSE35988.

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Acknowledgements

The authors thank the patients and families who participated in the rapid autopsy program. The authors thank C. Kumar, J. Shendure, M. Chaisson and A. Mortazavi for assistance with next-generation sequencing data analysis, K. Giles for assistance with manuscript preparation, and S. Varambally, A. Yocum, T. Barrette and M. Iyer for technical assistance. Supported in part by the National Institutes of Health S.P.O.R.E. (P50 CA69568) to K.J.P. and A.M.C., the Early Detection Research Network (U01 CA111275 and U01 CA113913) to A.M.C., R01CA132874 and the National Functional Genomics Center (W81XWH-09-2-0014) to A.M.C. A.M.C. and K.J.P. are supported by the Prostate Cancer Foundation and are American Cancer Society Clinical Research Professors and A. Alfred Taubman Scholars. A.M.C. is supported by the Doris Duke Foundation. D.R. Robinson is supported by a Department of Defense (DOD) Postdoctoral Award (W81XWH-11-1-0339). J.R.P. is supported by a DOD Predoctoral Award (PC094290). N.P. was supported by a UM SPORE career development award. S.A.T. and J.C.B. were supported by Young Investigator Awards from the Prostate Cancer Foundation.

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Author notes

  1. Catherine S. Grasso, Yi-Mi Wu and Dan R. Robinson: These authors contributed equally to this work.

Authors and Affiliations

  1. Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    Catherine S. Grasso, Yi-Mi Wu, Dan R. Robinson, Xuhong Cao, Saravana M. Dhanasekaran, Amjad P. Khan, Michael J. Quist, Xiaojun Jing, Robert J. Lonigro, J. Chad Brenner, Irfan A. Asangani, Bushra Ateeq, Sang Y. Chun, Javed Siddiqui, Lee Sam, Rohit Mehra, John R. Prensner, Nallasivam Palanisamy, Lakshmi P. Kunju, Daniel R. Rhodes, Kenneth J. Pienta, Arul M. Chinnaiyan & Scott A. Tomlins

  2. Department of Pathology, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    Catherine S. Grasso, Yi-Mi Wu, Dan R. Robinson, Saravana M. Dhanasekaran, Amjad P. Khan, Michael J. Quist, Xiaojun Jing, Irfan A. Asangani, Bushra Ateeq, Javed Siddiqui, Rohit Mehra, John R. Prensner, Nallasivam Palanisamy, Lakshmi P. Kunju, Daniel R. Rhodes, Arul M. Chinnaiyan & Scott A. Tomlins

  3. Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    Xuhong Cao & Arul M. Chinnaiyan

  4. Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    Robert J. Lonigro, Nallasivam Palanisamy, Kenneth J. Pienta & Arul M. Chinnaiyan

  5. Compendia Bioscience, Ann Arbor, 48104, Michigan, USA

    Matt Anstett & Daniel R. Rhodes

  6. Division of Biostatistics, Yale School of Public Health, New Haven, 06520, Connecticut, USA

    Gregory A. Ryslik

  7. Department of Computer Science & Center for Computational Molecular Biology, Brown University, Providence, 02912, Rhode Island, USA

    Fabio Vandin & Benjamin J. Raphael

  8. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    Kenneth J. Pienta

  9. Department of Urology, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    Kenneth J. Pienta & Arul M. Chinnaiyan

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  1. Catherine S. Grasso
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Contributions

S.A.T., K.J.P. and A.M.C. conceived the study. K.J.P. established the rapid autopsy program and K.J.P., R.M., J.S., L.P.K. and S.A.T. carried out rapid autopsies and assisted in tissue procurement and analysis. Y.-M.W., D.R. Robinson, X.C., N.P. and X.J. isolated DNA and RNA and carried out whole exome and transcriptome sequencing. X.J. and X.C. performed gene expression and aCGH. C.S.G., M.J.Q., L.S., R.J.L., G.A.R., F.V., B.J.R. and S.A.T. carried out bioinformatics and biostatistical analysis of sequencing data. Y.-M.W., S.M.D., D.R. Robinson, and S.Y.C. carried out Sanger-sequencing-based validation. R.J.L., M.A., D.R. Rhodes, X.C., X.J. and S.A.T. analysed gene expression profiling and aCGH data. A.P.K. and J.R.P. carried out studies on AR interactions and function. I.A.A. carried out ETS2 studies and Y.-M.W., B.A., D.R. Robinson and J.C.B. carried out FOXA1 studies. S.A.T., C.S.G. and A.M.C. wrote the manuscript, which was reviewed by all authors.

Corresponding authors

Correspondence to Kenneth J. Pienta or Arul M. Chinnaiyan.

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Competing interests

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. Rhodes 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. Rhodes 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.

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Grasso, C., Wu, YM., Robinson, D. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487, 239–243 (2012). https://doi.org/10.1038/nature11125

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