Polymorphisms of Antioxidant Enzymes SOD2 (rs4880) and GPX1 (rs1050450) Are Associated with Bladder Cancer Risk or Its Aggressiveness

Abstract

Background and Objectives: Oxidative stress induced by increased reactive oxygen species (ROS) production plays an important role in carcinogenesis. The entire urinary tract is continuously exposed to numerous potentially mutagenic environmental agents which generate ROS during their biotransformation. In first line defense against free radicals, antioxidant enzymes superoxide dismutase (SOD2) and glutathione peroxidase (GPX1) both have essential roles. Altered enzyme activity and decreased ability of neutralizing free oxygen radicals as a consequence of genetic polymorphisms in genes encoding these two enzymes are well described so far. This study aimed to investigate the association of GPX1 (rs1050450) and SOD2 (rs4880) genetic variants with the urothelial bladder cancer (UBC) risk independently and in combination with smoking. Furthermore, we aimed to determine whether the UBC stage and pathological grade were influenced by GPX1 and SOD2 polymorphisms. Material and Methods: The study population included 330 patients with UBC (mean age 65 ± 10.3 years) and 227 respective controls (mean age 63.4 ± 7.9 years). Single nucleotide polymorphism (SNP) of GPX1 (rs1050450) was analyzed using the PCR-RFLP, while SOD2 (rs4880) SNP was analyzed using the q-PCR method. Results: Our results showed that UBC risk was significantly increased among carriers of at least one variant SOD2 Val allele compared to the SOD2 Ala16Ala homozygotes (OR = 1.55, p = 0.03). Moreover, this risk was even more pronounced in smokers with at least one variant SOD2 Val allele, since they have even 7.5 fold higher UBC risk (OR = 7.5, p < 0.001). Considering GPX1 polymorphism, we have not found an association with UBC risk. However, GPX1 genotypes distribution differed significantly according to the tumor stage (p ˂ 0.049) and pathohistological grade (p ˂ 0.018). Conclusion: We found that SOD2 genetic polymorphism is associated with the risk of UBC development independently and in combination with cigarette smoking. Furthermore, we showed that GPX1 genetic polymorphism is associated with the aggressiveness of the disease.

The role of SOD2 and NOS2 genes in the molecular aspect of bladder cancer pathophysiology

“…Unfortunately, in our work, we did not find any correlation between 47 C > T (rs4880) SNP and the risk of BC development. On the other hand, Nikić et al (2023) and Hung et al (2004) found that the risk of urothelial BC was significantly increased among Val allele carriers compared to Ala/Ala homozygote in the Serbian and Italian populations 70 , 71 . Moreover, this risk was even greater in smokers with at least one variant of the SOD2 Val allele 70 .…”

“…On the other hand, Nikić et al (2023) and Hung et al (2004) found that the risk of urothelial BC was significantly increased among Val allele carriers compared to Ala/Ala homozygote in the Serbian and Italian populations 70 , 71 . Moreover, this risk was even greater in smokers with at least one variant of the SOD2 Val allele 70 . However, the results of a meta-analysis by Cao et al (2014) similar to our findings, showed no significant association between the SOD2 polymorphism and the risk of bladder cancer 72 .…”

Current Understanding of Human Polymorphism in Selenoprotein Genes: A Review of Its Significance as a Risk Biomarker

“…In addition, some studies investigated bladder cancer. A study in the Japanese population showed that the rs1050450 Pro/Leu genotype was highly associated with advanced tumor stage and increased the risk of bladder cancer compared with the control group [57]. The Ecuador sub-population that carries this polymorphism presented 3.8 times greater probability of developing bladder cancer than controls [53].…”

Microalgae as a Nutraceutical Tool to Antagonize the Impairment of Redox Status Induced by SNPs: Implications on Insulin Resistance

“…The GPX1 gene located on the nuclear chromosome 3p21.3 encodes for the most representative and abundant enzyme of the family: GPX1 [ 75 ]. The presence of the functional SNP rs1050450 on Gpx1 gene, induces the substitution of a cytosine with a thymine resulting in the replacement of a leucine with a proline at position 198 [ 76 ].…”