The mutational landscape of lethal castration-resistant prostate cancer

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, Matt Anstett, Rohit Mehra, John R. Prensner, Nallasivam Palanisamy, Gregory A. RyslikFabio Vandin, Benjamin J. Raphael, Lakshmi P. Kunju, Daniel R. Rhodes, Kenneth J. Pienta, Arul M. Chinnaiyan, Scott A. Tomlins

Research output: Contribution to journalArticle

1333 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)239-243
Number of pages5
JournalNature
Volume487
Issue number7406
DOIs
StatePublished - Jul 12 2012

All Science Journal Classification (ASJC) codes

  • General

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    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., ... Tomlins, S. A. (2012). The mutational landscape of lethal castration-resistant prostate cancer. Nature, 487(7406), 239-243. https://doi.org/10.1038/nature11125