rs1058205

This case-only study of 2,147 men (1,060 African Americans, 1,087 European Americans) examined whether GWAS-identified prostate cancer susceptibility SNPs are associated with disease aggressiveness. Four GWAS replication SNPs (rs2660753, rs13254738, rs10090154, rs2735839) and 7 flanking SNPs showed significant association (P<0.05) with prostate cancer aggressiveness across 3 genomic regions (3p12, 8q24, and 19q13). The KLK3 SNPs were notably associated with PSA levels in African Americans (p<0.001) and Gleason score in both populations, though associations were not consistent across racial groups.

Fine mapping study of the KLK3 locus (chromosome 19q13.33) in 3,522 prostate cancer cases and 3,338 controls identified three highly correlated SNPs (rs17632542, rs62113212, rs62113214) associated with nonaggressive prostate cancer (P = 4.72×10⁻⁵ to 5.74×10⁻⁵, OR = 0.68-0.69 per allele). The previously reported marker rs2735839 showed no significant association (P = 0.20). Baseline PSA levels were 43.7% lower in carriers of minor alleles at the three SNPs (P = 9.70×10⁻⁵), suggesting germline KLK3 variants influence PSA screening-detected prostate cancer.

Genome-wide association study identifying rs17632542 (Ile179Thr) in KLK3 gene as a strong prostate cancer susceptibility variant (combined P = 1.9 × 10⁻³⁴, OR = 0.66) across 10,405 cases and 10,681 controls. The variant was also associated with PSA levels and molecular dynamics modeling suggested it could alter protein stability or affect RNA splicing of KLK3.

Systematic literature review of 22 GWAS studies identifying 53 SNPs in 29 genomic loci associated with aggressive and progressive prostate cancer, particularly in low-grade disease. Functional analysis of 21 SNPs revealed involvement in the MYC/POU5F1B pathway (rs1447295, rs6983267, rs4242382), androgen receptor pathway (rs17021918, rs10486567, rs7679673, rs2939244), and PSA/KLK3 biomarkers (rs2735839, rs10993994). SNPs were integrated with somatic copy number aberration data, with 17 SNPs found in regions of recurrent CNAs predictive of progression; notably, rs1447295 and 7 other SNPs cluster in 8q24 gain regions harboring MYC.

A comprehensive resequencing analysis of the KLK15-KLK3-KLK2 locus on chromosome 19q13.33 in 78 individuals of European ancestry using 454 next-generation sequencing. The authors identified 555 polymorphic loci including 116 novel SNPs and 182 novel insertion/deletion polymorphisms. They discovered 11 coding variants in KLK3 (5 non-synonymous, 1 frameshift), 4 in KLK15, and 5 in KLK2. The key SNP rs2735839 lies in a region of relatively low linkage disequilibrium; two markers (rs2569735, rs1058205) in high LD (r²≥0.8) with rs2735839 were identified. This catalog of common genetic variation provides a foundation for fine-mapping studies of prostate cancer susceptibility and PSA regulation.

This systematic review identified 53 unique SNPs in 29 genomic loci associated with aggressive prostate cancer progression and poor outcomes from GWAS studies. Functional studies implicated 21 SNPs as modulating the androgen receptor pathway, MYC oncogene, and PSA-related genes, with rs1447295 and rs10993994 being replicated across multiple populations and associated with unfavorable pathological features in low-grade prostate cancer.