Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus
Kai Zhang; Johanna Schleutker; Xiaoyue Wang; Gong-Hong Wei; The PRACTICAL Consortium; Yuehong Yang; Sara Pereira Cruz; Csilla Sipeky; Liguo Wang; Qin Zhang; Anssi Auvinen; Markku H. Vaarala; Qilai Huang; Aki Manninen; Liang Wang; Nikolaos Giannareas; Ji-Han Xia; Jing Zhu; Hang-Mao Lee; Peng Zhang; Sufyan Suleman; Ping Gao; Teuvo L.J. Tammela; Song Liu; Xiao-Ming Dong
Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus
Kai Zhang
Johanna Schleutker
Xiaoyue Wang
Gong-Hong Wei; The PRACTICAL Consortium
Yuehong Yang
Sara Pereira Cruz
Csilla Sipeky
Liguo Wang
Qin Zhang
Anssi Auvinen
Markku H. Vaarala
Qilai Huang
Aki Manninen
Liang Wang
Nikolaos Giannareas
Ji-Han Xia
Jing Zhu
Hang-Mao Lee
Peng Zhang
Sufyan Suleman
Ping Gao
Teuvo L.J. Tammela
Song Liu
Xiao-Ming Dong
CELL PRESS
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042719499
https://urn.fi/URN:NBN:fi-fe2021042719499
Tiivistelmä
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.
Kokoelmat
- Rinnakkaistallenteet [19207]