Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus

被引：115

作者：

Gao, Ping ^{[1
]}

Xia, Ji-Han ^{[1
]}

Sipeky, Csilla ^{[2
]}

Dong, Xiao-Ming ^{[1
]}

Zhang, Qin ^{[1
]}

Yang, Yuehong ^{[1
]}

Zhang, Peng ^{[3
]}

Cruz, Sara Pereira ^{[1
]}

Zhang, Kai ^{[1
]}

Zhu, Jing

Lee, Hang-Mao ^{[1
]}

Suleman, Sufyan ^{[1
]}

Giannareas, Nikolaos ^{[1
]}

Liu, Song ^{[4
]}

Tammela, Teuvo L. J. ^{[5
,6
]}

Auvinen, Anssi ^{[7
]}

Wang, Xiaoyue ^{[4
]}

Huang, Qilai ^{[8
]}

Wang, Liguo ^{[9
]}

Manninen, Aki ^{[1
]}

Vaarala, Markku H. ^{[10
,11
]}

Wang, Liang

Schleutker, Johanna ^{[2
,12
]}

Wei, Gong-Hong ^{[1
]}

机构：

[1] Univ Oulu, Bioctr Oulu, Fac Biochem & Mol Med, Oulu 90014, Finland

[2] Univ Turku, Inst Biomed, Turku 20014, Finland

[3] Med Coll Wisconsin, MCW Canc Ctr, Dept Pathol, Milwaukee, WI 53226 USA

[4] Chinese Acad Med Sci, Peking Union Med Coll, Inst Basic Med Sci, State Key Lab Med Mol Biol Ctr Bioinformat, Beijing 100005, Peoples R China

[5] Tampere Univ Hosp, Dept Urol, Tampere, Finland

[6] Univ Tampere, Med Sch, Tampere 33521, Finland

[7] Univ Tampere, Sch Hlth Sci, Tampere 33520, Finland

[8] Shandong Univ, Sch Life Sci, Jinan 250012, Shandong, Peoples R China

[9] Mayo Clin, Coll Med, Div Biomed Stat & Informat, Rochester, MN 55905 USA

[10] Oulu Univ Hosp, Oulu 90014, Finland

[11] Univ Oulu, Med Res Ctr Oulu, Oulu 90014, Finland

[12] Turku Univ Hosp, Div Lab, Med Genet, Turku 20521, Finland

来源：

CELL | 2018年 / 174卷 / 03期

基金：

芬兰科学院;

关键词：

LONG NONCODING RNAS; EXPRESSION; RISK; SEQ; CISTROME; ALLELE; GENES;

D O I：

10.1016/j.cell.2018.06.003

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Genome-wide association studies (GWAS) have identified rs11672691 at 19q13 associated with aggressive prostate cancer (PCa). Here, we independently confirmed the finding in a cohort of 2,738 PCa patients and discovered the biological mechanism underlying this association. We found an association of the aggressive PCa-associated allele G of rs11672691 with elevated transcript levels of two biologically plausible candidate genes, PCAT19 and CEACAM21, implicated in PCa cell growth and tumor progression. Mechanistically, rs11672691 resides in an enhancer element and alters the binding site of HOXA2, a novel oncogenic transcription factor with prognostic potential in PCa. Remarkably, CRISPR/Cas9-mediated single-nucleotide editing showed the direct effect of rs11672691 on PCAT19 and CEACAM21 expression and PCa cellular aggressive phenotype. Clinical data demonstrated synergistic effects of rs11672691 genotype and PCAT19/CEACAM21 gene expression on PCa prognosis. These results provide a plausible mechanism for rs11672691 associated with aggressive PCa and thus lay the ground work for translating this finding to the clinic.

引用

页码：576 / +

页数：32

共 51 条

[1] The Molecular Taxonomy of Primary Prostate Cancer [J].

Abeshouse, Adam ;

Ahn, Jaeil ;

Akbani, Rehan ;

Ally, Adrian ;

Amin, Samirkumar ;

Andry, Christopher D. ;

Annala, Matti ;

Aprikian, Armen ;

Armenia, Joshua ;

Arora, Arshi ;

Auman, J. Todd ;

Balasundaram, Miruna ;

Balu, Saianand ;

Barbieri, Christopher E. ;

Bauer, Thomas ;

Benz, Christopher C. ;

Bergeron, Alain ;

Beroukhim, Rameen ;

Berrios, Mario ;

Bivol, Adrian ;

Bodenheimer, Tom ;

Boice, Lori ;

Bootwalla, Moiz S. ;

dos Reis, Rodolfo Borges ;

Boutros, Paul C. ;

Bowen, Jay ;

Bowlby, Reanne ;

Boyd, Jeffrey ;

Bradley, Robert K. ;

Breggia, Anne ;

Brimo, Fadi ;

Bristow, Christopher A. ;

Brooks, Denise ;

Broom, Bradley M. ;

Bryce, Alan H. ;

Bubley, Glenn ;

Burks, Eric ;

Butterfield, Yaron S. N. ;

Button, Michael ;

Canes, David ;

Carlotti, Carlos G. ;

Carlsen, Rebecca ;

Carmel, Michel ;

Carroll, Peter R. ;

Carter, Scott L. ;

Cartun, Richard ;

Carver, Brett S. ;

Chan, June M. ;

Chang, Matthew T. ;

Chen, Yu .

CELL, 2015, 163 (04) :1011-1025

[2] Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting [J].

Aguirre, Andrew J. ;

Meyers, Robin M. ;

Weir, Barbara A. ;

Vazquez, Francisca ;

Zhang, Cheng-Zhong ;

Ben-David, Uri ;

Cook, April ;

Ha, Gavin ;

Harrington, William F. ;

Doshi, Mihir B. ;

Kost-Alimova, Maria ;

Gill, Stanley ;

Xu, Han ;

Ali, Levi D. ;

Jiang, Guozhi ;

Pantel, Sasha ;

Lee, Yenarae ;

Goodale, Amy ;

Cherniack, Andrew D. ;

Oh, Coyin ;

Kryukov, Gregory ;

Cowley, Glenn S. ;

Garraway, Levi A. ;

Stegmaier, Kimberly ;

Roberts, Charles W. ;

Golub, Todd R. ;

Meyerson, Matthew ;

Root, David E. ;

Tsherniak, Aviad ;

Hahn, William C. .

CANCER DISCOVERY, 2016, 6 (08) :914-929

[3] A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer [J].

Al Olama, Ali Amin ;

Kote-Jarai, Zsofia ;

Berndt, Sonja I. ;

Conti, David V. ;

Schumacher, Fredrick ;

Han, Ying ;

Benlloch, Sara ;

Hazelett, Dennis J. ;

Wang, Zhaoming ;

Saunders, Ed ;

Leongamornlert, Daniel ;

Lindstrom, Sara ;

Jugurnauth-Little, Sara ;

Dadaev, Tokhir ;

Tymrakiewicz, Malgorzata ;

Stram, Daniel O. ;

Rand, Kristin ;

Wan, Peggy ;

Stram, Alex ;

Sheng, Xin ;

Pooler, Loreall C. ;

Park, Karen ;

Xia, Lucy ;

Tyrer, Jonathan ;

Kolonel, Laurence N. ;

Le Marchand, Loic ;

Hoover, Robert N. ;

Machiela, Mitchell J. ;

Yeager, Merideth ;

Burdette, Laurie ;

Chung, Charles C. ;

Hutchinson, Amy ;

Yu, Kai ;

Goh, Chee ;

Ahmed, Mahbubl ;

Govindasami, Koveela ;

Guy, Michelle ;

Tammela, Teuvo L. J. ;

Auvinen, Anssi ;

Wahlfors, Tlina ;

Schleutker, Johanna ;

Visakorpi, Tapio ;

Leinonen, Katri A. ;

Xu, Jianfeng ;

Aly, Markus ;

Donovan, Jenny ;

Travis, Ruth C. ;

Key, Tim J. ;

Siddiq, Afshan ;

Canzian, Federico .

NATURE GENETICS, 2014, 46 (10) :1103-1109

[4] A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease [J].

Al Olama, Ali Amin ;

Kote-Jarai, Zsofia ;

Schumacher, Fredrick R. ;

Wiklund, Fredrik ;

Berndt, Sonja I. ;

Benlloch, Sara ;

Giles, Graham G. ;

Severi, Gianluca ;

Neal, David E. ;

Hamdy, Freddie C. ;

Donovan, Jenny L. ;

Hunter, David J. ;

Henderson, Brian E. ;

Thun, Michael J. ;

Gaziano, Michael ;

Giovannucci, Edward L. ;

Siddiq, Afshan ;

Travis, Ruth C. ;

Cox, David G. ;

Canzian, Federico ;

Riboli, Elio ;

Key, Timothy J. ;

Andriole, Gerald ;

Albanes, Demetrius ;

Hayes, Richard B. ;

Schleutker, Johanna ;

Auvinen, Anssi ;

Tammela, Teuvo L. J. ;

Weischer, Maren ;

Stanford, Janet L. ;

Ostrander, Elaine A. ;

Cybulski, Cezary ;

Lubinski, Jan ;

Thibodeau, Stephen N. ;

Schaid, Daniel J. ;

Sorensen, Karina D. ;

Batra, Jyotsna ;

Clements, Judith A. ;

Chambers, Suzanne ;

Aitken, Joanne ;

Gardiner, Robert A. ;

Maier, Christiane ;

Vogel, Walther ;

Doerk, Thilo ;

Brenner, Hermann ;

Habuchi, Tomonori ;

Ingles, Sue ;

John, Esther M. ;

Dickinson, Joanne L. ;

Cannon-Albright, Lisa .

HUMAN MOLECULAR GENETICS, 2013, 22 (02) :408-415

[5] DOCK4 and CEACAM21 as novel schizophrenia candidate genes in the Jewish population [J].

Alkelai, Anna ;

Lupoli, Sara ;

Greenbaum, Lior ;

Kohn, Yoav ;

Kanyas-Sarner, Kyra ;

Ben-Asher, Edna ;

Lancet, Doron ;

Macciardi, Fabio ;

Lerer, Bernard .

INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, 2012, 15 (04) :459-469

[6] Identification of the Transcription Factor Single-Minded Homologue 2 as a Potential Biomarker and Immunotherapy Target in Prostate Cancer [J].

Arredouani, Mohamed S. ;

Lu, Bin ;

Bhasin, Manoj ;

Eljanne, Miriam ;

Yue, Wen ;

Mosquera, Juan-Miguel ;

Bubley, Glenn J. ;

Li, Vivian ;

Rubin, Mark A. ;

Libermann, Towia A. ;

Sanda, Martin G. .

CLINICAL CANCER RESEARCH, 2009, 15 (18) :5794-5802

[7] Two susceptibility loci identified for prostate cancer aggressiveness [J].

Berndt, Sonja I. ;

Wang, Zhaoming ;

Yeager, Meredith ;

Alavanja, Michael C. ;

Albanes, Demetrius ;

Amundadottir, Laufey ;

Andriole, Gerald ;

Freeman, Laura Beane ;

Campa, Daniele ;

Cancel-Tassin, Geraldine ;

Canzian, Federico ;

Cornu, Jean-Nicolas ;

Cussenot, Olivier ;

Diver, W. Ryan ;

Gapstur, Susan M. ;

Gronberg, Henrik ;

Haiman, Christopher A. ;

Henderson, Brian ;

Hutchinson, Amy ;

Hunter, David J. ;

Key, Timothy J. ;

Kolb, Suzanne ;

Koutros, Stella ;

Kraft, Peter ;

Le Marchand, Loic ;

Lindstroem, Sara ;

Machiela, Mitchell J. ;

Ostrander, Elaine A. ;

Riboli, Elio ;

Schumacher, Fred ;

Siddiq, Afshan ;

Stanford, Janet L. ;

Stevens, Victoria L. ;

Travis, Ruth C. ;

Tsilidis, Konstantinos K. ;

Virtamo, Jarmo ;

Weinstein, Stephanie ;

Wilkund, Fredrik ;

Xu, Jianfeng ;

Zheng, S. Lilly ;

Yu, Kai ;

Wheeler, William ;

Zhang, Han ;

Consortium, African Ancestry Prostate Canc G. W. A. S. ;

Sampson, Joshua ;

Black, Amanda ;

Jacobs, Kevin ;

Hoover, Robert N. ;

Tucker, Margaret ;

Chanock, Stephen J. .

NATURE COMMUNICATIONS, 2015, 6

[8] Expression patterns of CEACAM5 and CEACAM6 in primary and metastatic cancers [J].

Blumenthal, Rosalyn D. ;

Leon, Evelyn ;

Hansen, Hans J. ;

Goldenberg, David M. .

BMC CANCER, 2007, 7

[9] The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data [J].

Cerami, Ethan ;

Gao, Jianjiong ;

Dogrusoz, Ugur ;

Gross, Benjamin E. ;

Sumer, Selcuk Onur ;

Aksoy, Buelent Arman ;

Jacobsen, Anders ;

Byrne, Caitlin J. ;

Heuer, Michael L. ;

Larsson, Erik ;

Antipin, Yevgeniy ;

Reva, Boris ;

Goldberg, Arthur P. ;

Sander, Chris ;

Schultz, Nikolaus .

CANCER DISCOVERY, 2012, 2 (05) :401-404

[10] Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process [J].

Chandran, Uma R. ;

Ma, Changqing ;

Dhir, Rajiv ;

Bisceglia, Michelle ;

Lyons-Weiler, Maureen ;

Liang, Wenjing ;

Michalopoulos, George ;

Becich, Michael ;

Monzon, Federico A. .

BMC CANCER, 2007, 7 (1)

← 1 2 3 4 5 6 →