Association of Prostate Cancer Risk Loci with Disease Aggressiveness and Prostate Cancer–Specific Mortality

Abstract

Genome-wide association studies have detected more than 30 inherited prostate cancer risk variants. While clearly associated with risk, their relationship with clinical outcome, particularly prostate cancer–specific mortality, is less well known. We investigated whether the risk variants are associated with various measures of disease aggressiveness and prostate cancer–specific mortality. In a cohort of 3,945 men of European ancestry with prostate cancer, we genotyped 36 single nucleotide polymorphisms (SNP): 35 known prostate cancer risk variants and one SNP (rs4054823) that was recently reported to be associated with prostate cancer aggressiveness. The majority of subjects had a diagnosis of prostate cancer between 1995 and 2004, and the cohort included a total of 580 prostate cancer–specific deaths. We evaluated associations between the 36 polymorphisms and prostate cancer survival, as well as other clinical parameters including age at diagnosis, prostate-specific antigen (PSA) at diagnosis, and Gleason score. Two SNPs, rs2735839 at chromosome 19q13 and rs7679673 at 4q24, were associated with prostate cancer–specific survival (P = 7 × 10−4 and 0.014, respectively). A total of 12 SNPs were associated with other variables (P < 0.05): age at diagnosis, PSA at diagnosis, Gleason score, and/or disease aggressiveness based on D’Amico criteria. Genotype status at rs4054823 was not associated with aggressiveness or outcome. Our results identify two common polymorphisms associated with prostate cancer–specific mortality.

The Prostate Cancer Susceptibility Variant rs2735839 Near KLK3 Gene Is Associated with Aggressive Prostate Cancer and Can Stratify Gleason Score 7 Patients

“…Nevertheless, in Pomerantz and colleagues’ study including the largest number (580) of PCa-specific deaths (7), the variant allele (A) at rs2735839 was significantly associated with PCa-specific mortality, consistent with our observation that the variant allele was associated with aggressive diseases, supporting the prognostic value of this SNP.…”

“…It was reported that this SNP, located at 19q13, was associated with GS (6, 7) and disease aggressiveness (6, 7, 29). We also observed that the variant allele (A) at rs2735839 was associated with more aggressive disease in patients with clinically localized PCa.…”

“…Xu and colleagues found that the frequency of the allele (A) at rs2735839 was 0.11 in 528 men with less aggressive PCa, compared to 0.14 in 1,017 men with more aggressive disease (defined as pathologic GS ≥7, pathologic T3 disease or higher, or lymph node or distant metastasis in that study) in a series of patients treated with radical prostatectomy (29). In addition, Pomerantz and colleagues reported that the allele (A) at rs2735839 was associated with increased biopsy-proven GS and high risk of recurrence according to the D'Amico system in a study of 3,945 PCa patients (7). Furthermore, Kadar and colleagues reported that there was a significant increasing trend of A allele frequency among pathology-proved GS ≤6, GS 3+4, GS 4+3, and GS ≥8 diseases in 5749 cases underdoing prostatectomy (6).…”

“…However, a recent study showed that the association of KLK3 variants with PSA level cannot completely explain their association with PCa risk and suggests other independent effect of KLK3 variants on PCa aggressiveness and prognosis (37). Notably, it has been reported that the variant allele (A) at rs2735839 is associated with increased PCa-specific mortality in two independent studies (7, 38). Further analysis of the relationships among rs2735839, PSA level, and PCa risk is warranted in the context of inclusion of multiple factors related to PSA level.…”

The identification of trans-associations between prostate cancer GWAS SNPs and RNA expression differences in tumor-adjacent stroma

“…A total of 4030 such genes were identified. A second literature search of GWA studies of prostate cancer was conducted through the electronic database PubMed [2–14, 18, 40–43] covering a total of ~40000 prostate cancer cases, identifying more than 70 susceptible SNPs that were reported to have significant association with prostate cancer. 35 SNPs were selected and summarized in Supplementary Tables S2 and S3 for eQTL analysis.…”