• Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90014 Oulu, Finland.
• Institute of Biomedicine, University of Turku, 20014 Turku, Finland.
• Department of Pathology, MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
• State Key Laboratory of Medical Molecular Biology, Center for Bioinformatics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, 100005 Beijing, China.
• Department of Urology, Tampere University Hospital and Medical School, University of Tampere, 33521 Tampere, Finland.
• University of Tampere, School of Health Sciences, 33520 Tampere, Finland.
• School of Life Science, Shandong University, 250012 Jinan, China.
• Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
• Oulu University Hospital, 90014 Oulu, Finland; Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90014 Oulu, Finland.
• Institute of Biomedicine, University of Turku, 20014 Turku, Finland; Medical Genetics, Division of Laboratory, Turku University Hospital, 20521 Turku, Finland.

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.