Novel prostate cancer susceptibility gene SP6 predisposes patients to aggressive disease

Prostate cancer (PrCa) is one of the most common cancers in men, but little is known about factors affecting its clinical outcomes. Genome-wide association studies have identified more than 170 germline susceptibility loci, but most of them are not associated with aggressive disease. We performed a genome-wide analysis of 185,478 SNPs in Finnish samples (2738 cases, 2400 controls) from the international Collaborative Oncological Gene-Environment Study (iCOGS) to find underlying PrCa risk variants. We identified a total of 21 common, low-penetrance susceptibility loci, including 10 novel variants independently associated with PrCa risk. Novel risk loci were located in the 8q24 (CASC8 rs16902147, OR 1.86, p_adj = 3.53 × 10^-8 and rs58809953, OR 1.71, p_adj = 4.00 × 10^-6; intergenic rs79012498, OR 1.81, p_adj = 4.26 × 10^-8), 17q21 (SP6 rs2074187, OR 1.66, p_adj = 3.75 × 10^-5), 11q13 (rs12795301, OR 1.42, p_adj = 2.89 × 10^-5) and 8p21 (rs995432, OR 1.38, p_adj = 3.00 × 10^-11) regions. Here, we describe SP6, a transcription factor gene, as a new, potentially high-risk gene for PrCa. The intronic variant rs2074187 in SP6 was associated not only with overall susceptibility to PrCa (OR 1.66) but also with a higher odds ratio for aggressive PrCa (OR 1.89) and lower odds for non-aggressive PrCa (OR 1.43). Furthermore, the new intergenic variant rs79012498 at 8q24 conferred risk for aggressive PrCa. Our findings highlighted the power of a population-stratified approach to identify novel, clinically actionable germline PrCa risk loci and strongly suggested SP6 as a new PrCa candidate gene that may be involved in the pathogenesis of PrCa.