The mutational landscape of lethal castration-resistant prostate cancer

被引：2053

作者：

Grasso, Catherine S. ^{[1
,2
]}

Wu, Yi-Mi ^{[1
,2
]}

Robinson, Dan R. ^{[1
,2
]}

Cao, Xuhong ^{[1
,3
]}

Dhanasekaran, Saravana M. ^{[1
,2
]}

Khan, Amjad P. ^{[1
,2
]}

Quist, Michael J. ^{[1
,2
]}

Jing, Xiaojun ^{[1
,2
]}

Lonigro, Robert J. ^{[1
,4
]}

Brenner, J. Chad ^{[1
]}

Asangani, Irfan A. ^{[1
,2
]}

Ateeq, Bushra ^{[1
,2
]}

Chun, Sang Y. ^{[1
]}

Siddiqui, Javed ^{[1
,2
]}

Sam, Lee ^{[1
]}

Anstett, Matt ^{[5
]}

Mehra, Rohit ^{[1
,2
]}

Prensner, John R. ^{[1
,2
]}

Palanisamy, Nallasivam ^{[1
,2
,4
]}

Ryslik, Gregory A. ^{[6
]}

Vandin, Fabio ^{[7
,8
]}

Raphael, Benjamin J. ^{[7
,8
]}

Kunju, Lakshmi P. ^{[1
,2
]}

Rhodes, Daniel R. ^{[1
,2
,5
]}

Pienta, Kenneth J. ^{[1
,4
,9
,10
]}

Chinnaiyan, Arul M. ^{[1
,2
,3
,4
,10
]}

Tomlins, Scott A. ^{[1
,2
]}

机构：

[1] Univ Michigan, Sch Med, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Sch Med, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Sch Med, Comprehens Canc Ctr, Ann Arbor, MI 48109 USA

[5] Compendia Biosci, Ann Arbor, MI 48104 USA

[6] Yale Sch Publ Hlth, Div Biostat, New Haven, CT 06520 USA

[7] Brown Univ, Dept Comp Sci, Providence, RI 02912 USA

[8] Brown Univ, Ctr Computat Mol Biol, Providence, RI 02912 USA

[9] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA

[10] Univ Michigan, Sch Med, Dept Urol, Ann Arbor, MI 48109 USA

来源：

NATURE | 2012年 / 487卷 / 7406期

基金：

美国国家卫生研究院; 美国国家科学基金会;

关键词：

ANDROGEN RECEPTOR; FOXA1; NETWORK; FUSIONS; BINDING;

D O I：

10.1038/nature11125

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 mutations(2-4). 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.

引用

页码：239 / 243

页数：5

共 23 条

[1] Antitumor Activity with CYP17 Blockade Indicates That Castration-Resistant Prostate Cancer Frequently Remains Hormone Driven [J].

Attard, Gerhardt ;

Reid, Alison H. M. ;

Olmos, David ;

de Bono, Johann S. .

CANCER RESEARCH, 2009, 69 (12) :4937-4940

[2] Integrated genomic analyses of ovarian carcinoma [J].

Bell, D. ;

Berchuck, A. ;

Birrer, M. ;

Chien, J. ;

Cramer, D. W. ;

Dao, F. ;

Dhir, R. ;

DiSaia, P. ;

Gabra, H. ;

Glenn, P. ;

Godwin, A. K. ;

Gross, J. ;

Hartmann, L. ;

Huang, M. ;

Huntsman, D. G. ;

Iacocca, M. ;

Imielinski, M. ;

Kalloger, S. ;

Karlan, B. Y. ;

Levine, D. A. ;

Mills, G. B. ;

Morrison, C. ;

Mutch, D. ;

Olvera, N. ;

Orsulic, S. ;

Park, K. ;

Petrelli, N. ;

Rabeno, B. ;

Rader, J. S. ;

Sikic, B. I. ;

Smith-McCune, K. ;

Sood, A. K. ;

Bowtell, D. ;

Penny, R. ;

Testa, J. R. ;

Chang, K. ;

Dinh, H. H. ;

Drummond, J. A. ;

Fowler, G. ;

Gunaratne, P. ;

Hawes, A. C. ;

Kovar, C. L. ;

Lewis, L. R. ;

Morgan, M. B. ;

Newsham, I. F. ;

Santibanez, J. ;

Reid, J. G. ;

Trevino, L. R. ;

Wu, Y. -Q. ;

Wang, M. .

NATURE, 2011, 474 (7353) :609-615

[3] The genomic complexity of primary human prostate cancer [J].

Berger, Michael F. ;

Lawrence, Michael S. ;

Demichelis, Francesca ;

Drier, Yotam ;

Cibulskis, Kristian ;

Sivachenko, Andrey Y. ;

Sboner, Andrea ;

Esgueva, Raquel ;

Pflueger, Dorothee ;

Sougnez, Carrie ;

Onofrio, Robert ;

Carter, Scott L. ;

Park, Kyung ;

Habegger, Lukas ;

Ambrogio, Lauren ;

Fennell, Timothy ;

Parkin, Melissa ;

Saksena, Gordon ;

Voet, Douglas ;

Ramos, Alex H. ;

Pugh, Trevor J. ;

Wilkinson, Jane ;

Fisher, Sheila ;

Winckler, Wendy ;

Mahan, Scott ;

Ardlie, Kristin ;

Baldwin, Jennifer ;

Simons, Jonathan W. ;

Kitabayashi, Naoki ;

MacDonald, Theresa Y. ;

Kantoff, Philip W. ;

Chin, Lynda ;

Gabriel, Stacey B. ;

Gerstein, Mark B. ;

Golub, Todd R. ;

Meyerson, Matthew ;

Tewari, Ashutosh ;

Lander, Eric S. ;

Getz, Gad ;

Rubin, Mark A. ;

Garraway, Levi A. .

NATURE, 2011, 470 (7333) :214-220

[4] Distinct Genomic Aberrations Associated with ERG Rearranged Prostate Cancer [J].

Demichelis, Francesca ;

Setlur, Sunita R. ;

Beroukhim, Rameen ;

Perner, Sven ;

Korbel, Jan O. ;

LaFargue, Christopher J. ;

Pflueger, Dorothee ;

Pina, Cara ;

Hofer, Matthias D. ;

Sboner, Andrea ;

Svensson, Maria A. ;

Rickman, David S. ;

Urban, Alex ;

Snyder, Michael ;

Meyerson, Matthew ;

Lee, Charles ;

Gerstein, Mark B. ;

Kuefer, Rainer ;

Rubin, Mark A. .

GENES CHROMOSOMES & CANCER, 2009, 48 (04) :366-380

[5] The role of hepatocyte nuclear factor-3α (forkhead box A1) and androgen receptor in transcriptional regulation of prostatic genes [J].

Gao, N ;

Zhang, JF ;

Rao, MA ;

Case, TC ;

Mirosevich, J ;

Wang, YQ ;

Jin, RJ ;

Gupta, A ;

Rennie, PS ;

Matusik, RJ .

MOLECULAR ENDOCRINOLOGY, 2003, 17 (08) :1484-1507

[6] Diverse somatic mutation patterns and pathway alterations in human cancers [J].

Kan, Zhengyan ;

Jaiswal, Bijay S. ;

Stinson, Jeremy ;

Janakiraman, Vasantharajan ;

Bhatt, Deepali ;

Stern, Howard M. ;

Yue, Peng ;

Haverty, Peter M. ;

Bourgon, Richard ;

Zheng, Jianbiao ;

Moorhead, Martin ;

Chaudhuri, Subhra ;

Tomsho, Lynn P. ;

Peters, Brock A. ;

Pujara, Kanan ;

Cordes, Shaun ;

Davis, David P. ;

Carlton, Victoria E. H. ;

Yuan, Wenlin ;

Li, Li ;

Wang, Weiru ;

Eigenbrot, Charles ;

Kaminker, Joshua S. ;

Eberhard, David A. ;

Waring, Paul ;

Schuster, Stephan C. ;

Modrusan, Zora ;

Zhang, Zemin ;

Stokoe, David ;

de Sauvage, Frederic J. ;

Faham, Malek ;

Seshagiri, Somasekar .

NATURE, 2010, 466 (7308) :869-U103

[7] Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers [J].

Kumar, Akash ;

White, Thomas A. ;

MacKenzie, Alexandra P. ;

Clegg, Nigel ;

Lee, Choli ;

Dumpit, Ruth F. ;

Coleman, Ilsa ;

Ng, Sarah B. ;

Salipante, Stephen J. ;

Rieder, Mark J. ;

Nickerson, Deborah A. ;

Corey, Eva ;

Lange, Paul H. ;

Morrissey, Colm ;

Vessella, Robert L. ;

Nelson, Peter S. ;

Shendure, Jay .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (41) :17087-17092

[8] Detection of Somatic Copy Number Alterations in Cancer Using Targeted Exome Capture Sequencing [J].

Lonigro, Robert J. ;

Grasso, Catherine S. ;

Robinson, Dan R. ;

Jing, Xiaojun ;

Wu, Yi-Mi ;

Cao, Xuhong ;

Quist, Michael J. ;

Tomlins, Scott A. ;

Pienta, Kenneth J. ;

Chinnaiyan, Arul M. .

NEOPLASIA, 2011, 13 (11) :1019-U45

[9] FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription [J].

Lupien, Mathieu ;

Eeckhoute, Jerome ;

Meyer, Clifford A. ;

Wang, Qianben ;

Zhang, Yong ;

Li, Wei ;

Carroll, Jason S. ;

Liu, X. Shirley ;

Brown, Myles .

CELL, 2008, 132 (06) :958-970

[10] TMPRSS2:: ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer [J].

Perner, Sven ;

Demichelis, Francesca ;

Beroukhim, Rameen ;

Schmidt, Folke H. ;

Mosquera, Juan-Miguel ;

Setlur, Sunita ;

Tchinda, Joelle ;

Tomlins, Scott A. ;

Hofer, Matthias D. ;

Pienta, Kenneth G. ;

Kuefer, Rainer ;

Vessella, Robert ;

Sun, Xiao-Wei ;

Meyerson, Matthew ;

Lee, Charles ;

Sellers, William R. ;

Chinnaiyan, Arul M. ;

Rubin, Mark A. .

CANCER RESEARCH, 2006, 66 (17) :8337-8341

← 1 2 3 →