A1 Refereed original research article in a scientific journal
Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus
Authors: Ping Gao, Ji-Han Xia, Csilla Sipeky, Xiao-Ming Dong, Qin Zhang, Yuehong Yang, Peng Zhang, Sara Pereira Cruz, Kai Zhang, Jing Zhu, Hang-Mao Lee, Sufyan Suleman, Nikolaos Giannareas, Song Liu, Teuvo L.J. Tammela, Anssi Auvinen, Xiaoyue Wang, Qilai Huang, Liguo Wang, Aki Manninen, Markku H. Vaarala, Liang Wang, Johanna Schleutker, Gong-Hong Wei; The PRACTICAL Consortium
Publisher: CELL PRESS
Publication year: 2018
Journal: Cell
Journal name in source: CELL
Journal acronym: CELL
Volume: 174
Issue: 3
First page : 576
Last page: 589.e18
Number of pages: 32
ISSN: 0092-8674
eISSN: 1097-4172
DOI: https://doi.org/10.1016/j.cell.2018.06.003
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/34264026
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.
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