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

Abstract

Renal cell carcinoma (RCC) represents a group of histologically similar neoplasms with significant intratumor and intertumor genetic heterogeneity. Recognized risk factors for RCC development include smoking, hypertension, obesity, as well as von Hippel–Lindau (VHL) disease. Inactivation of VHL, deregulated nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) pathway, and altered redox homeostasis, together with changes in glutathione transferase (GST) profile, are considered as important contributing factors in RCC development and progression. Although the available results of both gene–gene and gene–environment analysis are quite heterogeneous, 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. Seemingly, GST genotyping could identify individuals with impaired detoxification in renal parenchyma that are at higher risk of developing RCC. In addition to well established roles of GSTs in conjugation and biotransformation of xenobiotics, GSTs have emerged as significant regulators of pathways determining cell proliferation and survival. Indeed, there are evidence in favor of GST significance, not only in terms of risk for RCC development, but also with respect to progression and prognosis. So far, GSTM1‐active genotype was confirmed to be an independent predictor of higher risk of overall mortality. Therefore, it is reasonable to assume that certain GST variants may assist in individual RCC risk assessment, as well as postoperative prognosis. Even more, GST profiling might contribute to development of personalized targeted therapy in RCC patients.

Development and Validation of a Nine-Redox-Related Long Noncoding RNA Signature in Renal Clear Cell Carcinoma

“…Redox plays an essential role in the pathogeneses and progression of tumors. Regulation of reactive oxygen species (ROS) production is crucial in highly proliferative cancer cells, owing to the presence of oncogenic mutations that promote aberrant metabolism and gene expression [42]. Cancer cells can produce ROS, which diffuses into the tumor microenvironment, then initiates stromal oxidative stress and autophagy, and leads to angiogenesis.…”

The role of redox homeostasis biomarkers in clear cell renal cell carcinoma development and progression

“…As previously noted, Nrf2 modulates the transcription of genes encoding phase-II detoxifying metabolism enzymes, as well as phase-III drug transporters (36). One of the main enzymes of interest are glutathione S-transferases (GST) as proteins with roles in numerous catalytic and noncatalytic processes (40). They offer protection from potentially injurious exogenous and endogenous electrophilic molecules by conjugating them with glutathione and thus facilitating their excretion via urine and bile (40).…”

The Polymorphisms in GSTO Genes (GSTO1 rs4925, GSTO2 rs156697, and GSTO2 rs2297235) Affect the Risk for Testicular Germ Cell Tumor Development: A Pilot Study

“…Glutathione S-transferases (GSTs) represent a large family of multifunctional proteins [ 9 , 10 ], constituting the first line of antioxidant defense along with glutathione peroxidase (GPX) and catalase [ 11 ]. Moreover, GSTs have proved themselves as valuable biomarkers of risk and prognosis for diseases hallmarked with disturbed redox homeostasis, such as cancers [ 12 , 13 , 14 ].…”