@article{e5a8d86d5fb44ab48b2d94d940352b93,
title = "Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus",
abstract = "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. A non-coding risk allele associated with aggressive prostate cancer creates a transcription factor binding site that in turn promotes oncogenesis by impacting expression of nearby genes.",
keywords = "CEACAM21, GWAS, HOXA2, PCAT19, aggressive prostate cancer, allele-specific DNA-binding of transcription factor, eQTL, risk stratification, rs11672691, single cell CRISPR/Cas9-mediated editing",
author = "{The PRACTICAL Consortium} and Ping Gao and Xia, {Ji Han} and Csilla Sipeky and Dong, {Xiao Ming} and Qin Zhang and Yuehong Yang and Peng Zhang and Cruz, {Sara Pereira} and Kai Zhang and Jing Zhu and Lee, {Hang Mao} and Sufyan Suleman and Nikolaos Giannareas and Song Liu and Tammela, {Teuvo L.J.} and Anssi Auvinen and Xiaoyue Wang and Qilai Huang and Liguo Wang and Aki Manninen and Vaarala, {Markku H.} and Liang Wang and Johanna Schleutker and Wei, {Gong Hong}",
note = "Funding Information: We thank Johanna Myllyharju, Kalervo Hiltunen, Peppi Karppinen, and Taina Pihlajaniemi for study support; Antti Viklund, Aira Erkkil{\"a}, Jaana Tr{\"a}skelin, Katri Pylk{\"a}s, Leena Keskitalo, Meeri Otsukka, Veli-Pekka Ronkainen, BCO Sequencing, and Imaging Core for technical service; Fredrik Wiklund, Johan Lindberg, and Thomas Whitington for eQTL data; and CSC-IT Center for Computing server and TCGA Research Network. This work was funded by the Academy of Finland ( 284618 and 279760 to G.-H.W., 251074 and 310115 to J.S.), the University of Oulu Strategic Funds (to G.-H.W.), the Jane and Aatos Erkko Foundation (to G.-H.W.), Finnish Cancer Foundation (to G.-H.W. and J.S.), Sigrid Juselius Foundation (to J.S.), Turku University Hospital ( M3002 and M4807 to J.S.), the NIH ( R01CA157881 to Liang Wang), and the China Scholarship Council fellowship ( 201206300074 to P.G.). Funding Information: We thank Johanna Myllyharju, Kalervo Hiltunen, Peppi Karppinen, and Taina Pihlajaniemi for study support; Antti Viklund, Aira Erkkil?, Jaana Tr?skelin, Katri Pylk?s, Leena Keskitalo, Meeri Otsukka, Veli-Pekka Ronkainen, BCO Sequencing, and Imaging Core for technical service; Fredrik Wiklund, Johan Lindberg, and Thomas Whitington for eQTL data; and CSC-IT Center for Computing server and TCGA Research Network. This work was funded by the Academy of Finland (284618 and 279760 to G.-H.W., 251074 and 310115 to J.S.), the University of Oulu Strategic Funds (to G.-H.W.), the Jane and Aatos Erkko Foundation (to G.-H.W.), Finnish Cancer Foundation (to G.-H.W. and J.S.), Sigrid Juselius Foundation (to J.S.), Turku University Hospital (M3002 and M4807 to J.S.), the NIH (R01CA157881 to Liang Wang), and the China Scholarship Council fellowship (201206300074 to P.G.). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = jul,
day = "26",
doi = "10.1016/j.cell.2018.06.003",
language = "English (US)",
volume = "174",
pages = "576--589.e18",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",
}