Combined <i>GSTM1-Null</i>, <i>GSTT1-Active</i>, <i>GSTA1 Low-Activity</i> and <i>GSTP1-Variant</i> Genotype Is Associated with Increased Risk of Clear Cell Renal Cell Carcinoma

<div><p>The aim of this study was to evaluate specific glutathione S-transferase (GST) gene variants as determinants of risk in patients with clear cell renal cell carcinoma (cRCC), independently or simultaneously with established RCC risk factors, as well as to discern whether phenotype changes reflect genotype-associated risk. <i>GSTA1</i>, <i>GSTM1</i>, <i>GSTP1</i> and <i>GSTT1</i> genotypes were determined in 199 cRCC patients and 274 matched controls. Benzo(a)pyrene diolepoxide (BPDE)-DNA adducts were determined in DNA samples obtained from cRCC patients by ELISA method. Significant association between <i>GST</i> genotype and risk of cRCC development was found for the <i>GSTM1-null</i> and <i>GSTP1-variant</i> genotype (p = 0.02 and p<0.001, respectively). Furthermore, 22% of all recruited cRCC patients were carriers of combined <i>GSTM1-null</i>, <i>GSTT1-active</i>, <i>GSTA1-low activity</i> and <i>GSTP1-variant</i> genotype, exhibiting 9.32-fold elevated cRCC risk compared to the reference genotype combination (p = 0.04). Significant association between <i>GST</i> genotype and cRCC risk in smokers was found only for the <i>GSTP1</i> genotype, while <i>GSTM1-null/GSTP1-variant/GSTA1 low-activity</i> genotype combination was present in 94% of smokers with cRCC, increasing the risk of cRCC up to 7.57 (p = 0.02). Furthermore, cRCC smokers with <i>GSTM1-null</i> genotype had significantly higher concentration of BPDE-DNA adducts in comparison with <i>GSTM1-active</i> cRCC smokers (p = 0.05). <i>GSTM1</i>, <i>GSTT1</i>, <i>GSTA1</i> and <i>GSTP1</i> polymorphisms might be associated with the risk of cRCC, with special emphasis on <i>GSTM1-null</i> and <i>GSTP1-variant</i> genotypes. Combined <i>GSTM1-null</i>, <i>GSTT1-active</i>, <i>GSTA1 low activity</i> and <i>GSTP1-variant</i> genotypes might be considered as “risk-carrying genotype combination” in cRCC.</p>