A rare 8q24 single nucleotide polymorphism (SNP) predisposes North American men to prostate cancer and possibly more aggressive disease.

Objective To assess the frequency of a novel prostate cancer-associated single nucleotide polymorphism (SNP), rs188140481, in a North American population and to evaluate the clinical significance of this variant including annotated prostatectomy pathology. Subjects and Methods We examined the frequency of the minor allele at rs188140481 in 4,299 North American men including 1,979 PC cases and 2,320 healthy volunteers. We compared the clinico-pathologic features of PC between carriers and non-carriers of the SNP. Results The rs188140481[A] SNP was present in 1.6% of the cohort; it was significantly more likely to be carried by men with PC than healthy controls (OR 3.14; 95% CI 1.85-5.35). After adjusting for age and PSA carriers were found 6.73-fold (95% CI 1.69-26.76) more likely to develop PC than non-carriers. Age at diagnosis, frequency of a positive family history of PC, and biochemical recurrence rates were similar between SNP carriers and non-carriers. Patients with the SNP had a proportionately higher frequency of stage ≥ T2c disease (29.5% vs. 20.1%; p = 0.13), Gleason ≥8 tumors (13.3% vs. 6.5%; p = 0.10), and extracapsular extension (28.9% vs. 18.8%; p = 0.12) compared to non-carriers. Conclusions rs188140481[A] is a rare SNP that confers greater risk of PC compared to SNPs identified by genome-wide association studies. Because of its low frequency, larger studies are needed to validate the prognostic significance of this locus, and associations with adverse pathology. Keywords: genetics, prostatic neoplasm, polymorphism, single nucleotide Introduction Prostate cancer (PC) is the most common non-skin cancer affecting men in the United States, with 238,590 new cases projected in 2013[1]. Genome-wide association (GWAS) and sequencing studies have recently generated rapid progress towards identifying genetic markers associated with increased PC risk[2]. Currently more than 77 different common single nucleotide polymorphisms (SNPs) have been identified on 11 different chromosomes that confer a modest risk of PC (OR: 1.12 - 2.04) in men of European ancestry[2-4]. The 8q24 region has emerged as a key region for PC susceptibility. In fact, it is often considered to be the genetic “hot-spot,” containing nine different PC-associated SNPs, within at least 5 distinct regions[5-9]. Recently, newer whole-genome sequencing (WGS) techniques have been used to identify rarer alleles associated with a far greater risk of developing PC and potentially more aggressive forms of the disease[10,11]. WGS has recently been employed to identify a novel SNP on 8q24 that is associated with PC in a predominantly European population[10]. This SNP was carried by only 1.1% of the men in that study. Although relatively rare, it was shown to confer a significantly greater risk of developing PC than previously identified loci (OR = 2.90). In the initial study, Gudmundsson and colleagues reported that this variant was associated with an earlier age of diagnosis (-1.26 years) and a trend toward more aggressive disease (p=0.08). Because this study focused on a cohort of European men undergoing various therapies for PC management, our objective was to further evaluate the clinical significance of this variant in a North American population, including annotated prostatectomy pathology and early follow-up for biochemical recurrence.