Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus

Abstract

<p id="P1">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 <i>PCAT19</i> and <i>CEACAM21</i>, 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 <i>PCAT19</i> and <i>CEACAM21</i> expression, and PCa cellular aggressive phenotype. Clinical data demonstrated synergistic effects of rs11672691 genotype and <i>PCAT19/CEACAM21</i> 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. </p><p class="first" id="P2"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/03687a5b-227e-4b67-9777-850a3ce6118e/PubMedCentral/image/nihms-977478-f0001.jpg"/> </div> </p><p id="P3">A non-coding risk allele associated with aggressive prostate cancer creates a transcription factor binding site which in turn promotes oncogenesis by impacting expression of nearby genes </p>