| Summary: | <i>Background and Objectives</i>: One of the most frequent genetic alterations reported to date in prostate cancer (PC) is aberrant methylation of glutathione transferase P1 (<i>GSTP1</i>). Taking into consideration the involvement of oxidative stress in PC pathogenesis and recent advances in scientific understanding of the role of <i>GSTP1*</i>Ala114Val rs1138272 polymorphism in carcinogenesis, we hypothesized that this single-nucleotide polymorphism (SNP) influences the risk of PC independently of, or in combination with, other GST polymorphisms, including <i>GSTP1*</i>IIe105Val rs1695 or <i>GSTM1</i> and <i>GSTT1</i> deletion polymorphisms. <i>Materials and Methods</i>: Genotyping was performed in 237 PC cases and in 236 age-matched controls by multiplex polymerase chain reaction (PCR) for deletion of GST polymorphisms and by quantitative PCR for SNPs. <i>Results</i>: We found that carriers of either <i>GSTP1</i>*Val (rs1138272) or <i>GSTP1</i>*Val (rs1695) variant alleles had a PC risk compared to individuals with both referent alleles (OR = 4.93, 95%CI: 2.89−8.40, <i>p</i> < 0.001 and OR = 1.8, 95%CI: 1.19−2.73, <i>p</i> = 0.006, respectively). Additionally, in a haplotype analysis we found that individuals with <i>GSTP1*C</i> haplotype, represented by both variant alleles <i>(GSTP1*Val rs1695 + GSTP1*Val rs1138272)</i>, had a 5.46 times higher risk of PC development compared to individuals with the most frequent haplotype (95%CI = 2.56−11.65, <i>p</i> < 0.001), suggesting a potential role of those variants in PC susceptibility. A regression analysis on the number of risk-associated alleles per individual (<i>GSTM1*active, GSTT1*null, GSTP1*Val rs1695</i> and <i>GSTP1*Val rs1138272</i>) showed a significant increase in the risk of developing PC, from 3.65-fold in carriers of two risk alleles (95%CI = 1.55−8.61, <i>p</i> = 0.003) to an approximately 12-fold increase in carriers of all four risk alleles (95%CI = 3.05−44.93, <i>p</i> < 0.001). <i>Conclusion</i>: Prostate cancer may be influenced by multiple glutathione transferase (GST) polymorphic genes, especially <i>GSTP1</i>, highlighting the role of gene−gene interactions in human susceptibility to this cancer.
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