ena-STUDY-Faculty of Biochemistry and Molecular medicine University of Oulu-26-03-2018-09:12:51:139-879
Biology and clinical implications of the 19q13 aggressive prostate cancer susceptibility locus
Genome-wide association studies (GWASs) have identified rs11672691 at 19q13 associated with aggressive prostate cancer (PCa). Here, we independently confirmed the finding in a cohort of 2738 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 mRNA levels of two biologically plausible candidate genes PCAT19 and CEACAM21, implicating 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 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 hence lay the ground work for translating this finding to the clinic.
Genome-wide association studies (GWASs) have identified rs11672691 at 19q13 associated with aggressive prostate cancer (PCa). Here, we independently confirmed the finding in a cohort of 2738 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 mRNA levels of two biologically plausible candidate genes PCAT19 and CEACAM21, implicating 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 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 hence lay the ground work for translating this finding to the clinic.