TY - JOUR
T1 - The mutational landscape of lethal castration-resistant prostate cancer
AU - Grasso, Catherine S.
AU - Wu, Yi Mi
AU - Robinson, Dan R.
AU - Cao, Xuhong
AU - Dhanasekaran, Saravana M.
AU - Khan, Amjad P.
AU - Quist, Michael J.
AU - Jing, Xiaojun
AU - Lonigro, Robert J.
AU - Brenner, J. Chad
AU - Asangani, Irfan A.
AU - Ateeq, Bushra
AU - Chun, Sang Y.
AU - Siddiqui, Javed
AU - Sam, Lee
AU - Anstett, Matt
AU - Mehra, Rohit
AU - Prensner, John R.
AU - Palanisamy, Nallasivam
AU - Ryslik, Gregory A.
AU - Vandin, Fabio
AU - Raphael, Benjamin J.
AU - Kunju, Lakshmi P.
AU - Rhodes, Daniel R.
AU - Pienta, Kenneth J.
AU - Chinnaiyan, Arul M.
AU - Tomlins, Scott A.
N1 - Funding Information:
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.
PY - 2012/7/12
Y1 - 2012/7/12
N2 - 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.
AB - 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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U2 - 10.1038/nature11125
DO - 10.1038/nature11125
M3 - Article
C2 - 22722839
AN - SCOPUS:84863723010
SN - 0028-0836
VL - 487
SP - 239
EP - 243
JO - Nature
JF - Nature
IS - 7406
ER -