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

Vesna M Coric,Marija G Matic,Ana R Savic Radojevic,Dejan P Dragicevic,Ljiljana M Bogdanovic,Tanja M Radic,Tatjana P Simic,Sanja M Radojevic-Skodric,Gordana M Basta-Jovanovic,Marija S Pljesa-Ercegovac,Tatjana D Pekmezovic,Zoran M Dzamic,Jose Crispin

doi:10.1371/journal.pone.0160570

Vesna M Coric, Marija G Matic + Show 11 more

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https://doi.org/10.1371/journal.pone.0160570

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Journal: PloS one	Publication Date: Aug 8, 2016
Citations: 17	License type: CC BY 4.0

Affiliation: University of Belgrade, Institute of Physics Belgrade

Abstract

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.

Highlights

Renal cell carcinoma (RCC), the most common adult renal neoplasm, accounts for 2–3% of all cancers and 2% of all cancer-related deaths [1,2,3]
The frequency of GSTM1-null genotype was higher (56%) in cell RCC (cRCC) patients than in controls (50%) and individuals with GSTM1-null genotype were at 2.07-fold higher risk of cRCC development (95%confidence intervals (CI):1.11–3.84, p = 0.02) (Table 3)
No significant association with cRCC risk was found for GSTT1-active genotype (OR = 1.08, 95%CI:0.52–2.27, p = 0.82)

Summary

Introduction

Renal cell carcinoma (RCC), the most common adult renal neoplasm, accounts for 2–3% of all cancers and 2% of all cancer-related deaths [1,2,3]. The main site for the initial glutathione conjugation of toxic compounds is generally assumed to be the liver, followed by a mandatory transfer of conjugates to the kidney [10]. This pathway results mainly in detoxification and elimination of glutathione conjugates by the kidney [11]. Some GSTs are associated with bio-activation of occupational hazards, such as trichloroethylene, chlorophenols and pesticides [12], where the glutathione conjugate is more reactive than the parent compound. It has been shown that the initial bio-activation step of some nephrocarcinogens can take place in the kidney itself [10,11]

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