Concomitance of Polymorphisms in Glutathione Transferase Omega Genes Is Associated with Risk of Clear Cell Renal Cell Carcinoma

Abstract

Glutathione S-transferases (GSTs), a superfamily of multifunctional enzymes, play an important role in the onset and progression of renal cell carcinoma (RCC). However, novel GST omega class (GSTO), consisting of GSTO1-1 and GSTO2-2 isoenzymes, has not been studied in RCC yet. Two coding single nucleotide polymorphisms (SNPs) supposedly affect their functions: GSTO1*C419A (rs4925) causing alanine to aspartate substitution (*A140D) and GSTO2*A424G (rs156697) causing asparagine to aspartate substitution (*N142D), and have been associated with several neurodegenerative diseases and cancers. Functional relevance of yet another GSTO2 polymorphism, identified at the 5' untranslated (5'UTR) gene region (GSTO2*A183G, rs2297235), has not been clearly discerned so far. Therefore, we aimed to assess the effect of specific GSTO1 and GSTO2 gene variants, independently and in interaction with established risk factors (smoking, obesity and hypertension) on the risk for the most aggressive RCC subtype, the clear cell RCC (ccRCC). Genotyping was performed in 239 ccRCC patients and 350 matched controls, while plasma levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, were determined by ELISA. As a result, combined effect of all three variant genotypes exhibited almost 3-fold risk of RCC development. Additionally, this association was confirmed at the haplotype level [variant GSTO1*A/GSTO2*G (rs156697)/GSTO2*G (rs2297235) haplotype], suggesting a potential role of those variants in propensity to RCC. Regarding the gene-environment interactions, variant GSTO2*G (rs156697) homozygous smokers are at higher ccRCC risk. Association in terms of oxidative DNA damage was found for GSTO2 polymorphism in 5'UTR and 8-OHdG. In conclusion, the concomitance of GSTO polymorphisms may influence ccRCC risk.

Glutathione transferase genotypes may serve as determinants of risk and prognosis in renal cell carcinoma

“…51 Seemingly, GST genotyping could identify individuals with impaired detoxification in renal parenchyma that are at higher risk of developing RCC. Although the available results of both gene-gene and gene-environment analysis are quite heterogeneous (Table 1), 46,49,[52][53][54][55][56][57][58][59][60] , they clearly indicate that certain GST genotypes may play a role as risk modifiers either individually or in combination with other Phase I or Phase II gene polymorphisms, as well as in subjects exposed to relevant substrates. Numerous studies attempted to discern whether GSTM1-null individuals are at risk of cancer development.…”

“…Associated individually 49,59 or in combination with other genotypes 49,59 Associated in combination with other genotypes [54][55][56]58 GSTP1-variant c Associated individually 46,49,57 or in smokers 46 or in combination with other genotypes 46,49,57 Associated in combination with other genotypes 54 GSTO1 variant c (rs4925) Associated in combination with GSTO2-variant alleles (rs156697, rs2297235) 60 No data available GSTO2-variant c (rs148697) Associated in smokers 60 No data available The data on the potential role of GSTA1 polymorphic expression in both onset and prognosis of RCC are limited. 46,57,62 Although the expression of GST alpha is predominantly found in clear cell RCC, 33 the results obtained found no significant association of GSTA1-low activity genotype (CT + TT, rs3957356), with increased risk for RCC.…”

“…46 Interestingly, combined effect of three variant GST omega genotypes was associated with the risk of RCC development and confirmed at the haplotype level (variant GSTO1*A (rs4925)/ GSTO2*G (rs156697)/GSTO2*G (rs2297235), suggesting a potential role of these genotypes in propensity to RCC. 60 Regarding the gene-environment interactions, smokers carriers of variant GSTO2*G (rs156697) seem to be at higher ccRCC risk, while association in terms of oxidative phenotype was found only for GSTO2 rs2297235 and a biomarker of oxidative DNA damage, 8-hydroxy-2 0 -deoxyguanosine (8-OHdG). 60…”

“…60 Regarding the gene-environment interactions, smokers carriers of variant GSTO2*G (rs156697) seem to be at higher ccRCC risk, while association in terms of oxidative phenotype was found only for GSTO2 rs2297235 and a biomarker of oxidative DNA damage, 8-hydroxy-2 0 -deoxyguanosine (8-OHdG). 60…”

“…GSTO2-variant c (rs2297235)Associated in combination with other GSTO-variant alleles (rs4925, rs156697)60 No data availablea Active, if at least one active allele present; b Null, if no active alleles present; c Variant, not being referent in observed setting.…”