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
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
收藏
页码:576 / +
页数:32
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