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 Alexander Ryslik & 7 others Fabio Vandin, Benjamin J. Raphael, Lakshmi P. Kunju, Daniel R. Rhodes, Kenneth J. Pienta, Arul M. Chinnaiyan, Scott A. Tomlins

Research output: Contribution to journalArticle

1166 Citations (Scopus)

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

Fingerprint

Castration
Prostatic Neoplasms
Androgen Receptors
Gene Fusion
Exome
Mutation
Mutation Rate
Transcriptome
Histones
Androgens
Chromatin
Autopsy
Neoplasms
Genome

All Science Journal Classification (ASJC) codes

  • General

Cite this

Grasso, C. S., Wu, Y. M., Robinson, D. R., Cao, X., Dhanasekaran, S. M., Khan, A. P., ... Tomlins, S. A. (2012). The mutational landscape of lethal castration-resistant prostate cancer. Nature, 487(7406), 239-243. https://doi.org/10.1038/nature11125
Grasso, Catherine S. ; Wu, Yi Mi ; Robinson, Dan R. ; Cao, Xuhong ; Dhanasekaran, Saravana M. ; Khan, Amjad P. ; Quist, Michael J. ; Jing, Xiaojun ; Lonigro, Robert J. ; Brenner, J. Chad ; Asangani, Irfan A. ; Ateeq, Bushra ; Chun, Sang Y. ; Siddiqui, Javed ; Sam, Lee ; Anstett, Matt ; Mehra, Rohit ; Prensner, John R. ; Palanisamy, Nallasivam ; Ryslik, Gregory Alexander ; Vandin, Fabio ; Raphael, Benjamin J. ; Kunju, Lakshmi P. ; Rhodes, Daniel R. ; Pienta, Kenneth J. ; Chinnaiyan, Arul M. ; Tomlins, Scott A. / The mutational landscape of lethal castration-resistant prostate cancer. In: Nature. 2012 ; Vol. 487, No. 7406. pp. 239-243.
@article{75ddbf8342ab41bf969081526aaac421,
title = "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.",
author = "Grasso, {Catherine S.} and Wu, {Yi Mi} and Robinson, {Dan R.} and Xuhong Cao and Dhanasekaran, {Saravana M.} and Khan, {Amjad P.} and Quist, {Michael J.} and Xiaojun Jing and Lonigro, {Robert J.} and Brenner, {J. Chad} and Asangani, {Irfan A.} and Bushra Ateeq and Chun, {Sang Y.} and Javed Siddiqui and Lee Sam and Matt Anstett and Rohit Mehra and Prensner, {John R.} and Nallasivam Palanisamy and Ryslik, {Gregory Alexander} and Fabio Vandin and Raphael, {Benjamin J.} and Kunju, {Lakshmi P.} and Rhodes, {Daniel R.} and Pienta, {Kenneth J.} and Chinnaiyan, {Arul M.} and Tomlins, {Scott A.}",
year = "2012",
month = "7",
day = "12",
doi = "10.1038/nature11125",
language = "English (US)",
volume = "487",
pages = "239--243",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7406",

}

Grasso, CS, Wu, YM, Robinson, DR, Cao, X, Dhanasekaran, SM, Khan, AP, Quist, MJ, Jing, X, Lonigro, RJ, Brenner, JC, Asangani, IA, Ateeq, B, Chun, SY, Siddiqui, J, Sam, L, Anstett, M, Mehra, R, Prensner, JR, Palanisamy, N, Ryslik, GA, Vandin, F, Raphael, BJ, Kunju, LP, Rhodes, DR, Pienta, KJ, Chinnaiyan, AM & Tomlins, SA 2012, 'The mutational landscape of lethal castration-resistant prostate cancer', Nature, vol. 487, no. 7406, pp. 239-243. https://doi.org/10.1038/nature11125

The mutational landscape of lethal castration-resistant prostate cancer. / Grasso, Catherine S.; Wu, Yi Mi; Robinson, Dan R.; Cao, Xuhong; Dhanasekaran, Saravana M.; Khan, Amjad P.; Quist, Michael J.; Jing, Xiaojun; Lonigro, Robert J.; Brenner, J. Chad; Asangani, Irfan A.; Ateeq, Bushra; Chun, Sang Y.; Siddiqui, Javed; Sam, Lee; Anstett, Matt; Mehra, Rohit; Prensner, John R.; Palanisamy, Nallasivam; Ryslik, Gregory Alexander; Vandin, Fabio; Raphael, Benjamin J.; Kunju, Lakshmi P.; Rhodes, Daniel R.; Pienta, Kenneth J.; Chinnaiyan, Arul M.; Tomlins, Scott A.

In: Nature, Vol. 487, No. 7406, 12.07.2012, p. 239-243.

Research output: Contribution to journalArticle

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 Alexander

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=84863723010&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863723010&partnerID=8YFLogxK

U2 - 10.1038/nature11125

DO - 10.1038/nature11125

M3 - Article

VL - 487

SP - 239

EP - 243

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7406

ER -

Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012 Jul 12;487(7406):239-243. https://doi.org/10.1038/nature11125