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

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. GSTA1, GSTM1, GSTP1 and GSTT1 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 GST genotype and risk of cRCC development was found for the GSTM1-null and GSTP1-variant genotype (p = 0.02 and p<0.001, respectively). Furthermore, 22% of all recruited cRCC patients were carriers of combined GSTM1-null, GSTT1-active, GSTA1-low activity and GSTP1-variant genotype, exhibiting 9.32-fold elevated cRCC risk compared to the reference genotype combination (p = 0.04). Significant association between GST genotype and cRCC risk in smokers was found only for the GSTP1 genotype, while GSTM1-null/GSTP1-variant/GSTA1 low-activity 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 GSTM1-null genotype had significantly higher concentration of BPDE-DNA adducts in comparison with GSTM1-active cRCC smokers (p = 0.05). GSTM1, GSTT1, GSTA1 and GSTP1 polymorphisms might be associated with the risk of cRCC, with special emphasis on GSTM1-null and GSTP1-variant genotypes. Combined GSTM1-null, GSTT1-active, GSTA1 low activity and GSTP1-variant genotypes might be considered as "risk-carrying genotype combination" in cRCC

<i>GST</i> genotypes in relation to the risk of cRCC.

<p><i>GST</i> genotypes in relation to the risk of cRCC.</p

Baseline characteristic of patients with cRCC and respective controls.

<p>Baseline characteristic of patients with cRCC and respective controls.</p

Combined effect of <i>GST</i> genotypes on risk of cRCC.

<p>Combined effect of <i>GST</i> genotypes on risk of cRCC.</p

<i>GST</i> genotypes in relation to the risk of cRCC.

<p><i>GST</i> genotypes in relation to the risk of cRCC.</p

The association between <i>GST</i> genotypes and the levels of BPDE-DNA adducts in cRCC smokers.

<p>The association between <i>GST</i> genotypes and the levels of BPDE-DNA adducts in cRCC smokers.</p

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></div

PCR: primer sequences, PCR conditions, restriction enzymes and fragment lengths.

<p>PCR: primer sequences, PCR conditions, restriction enzymes and fragment lengths.</p