Abstract
Simple SummaryTesticular cancer is the most common malignancy in the population of young and reproductively active men. The risk factors for its occurrence are not fully elucidated. Undescended testicle remains the main risk factor; however, more precise molecular studies associate genetic variations with susceptibility to testicular tumor development and progression. In this study, we found that specific variations in genes encoding antioxidant defense proteins confer risks of testicular cancer development and progression and, therefore, helps to identify subjects at higher risk, as well as those requiring additional diagnostics and more intensive forms of treatment.The simultaneous analysis of redox biomarkers and polymorphisms encoding for regulatory and catalytic antioxidant proteins was performed in order to evaluate their potential role in the development of testicular germ cell tumor (GCT), as well as the progression of the disease. NRF2 (rs6721961), GSTM3 (rs1332018), SOD2 (rs4880) and GPX3 (rs8177412) polymorphisms were assessed in 88 patients with testicular GCT (52 with seminoma) and 88 age-matched controls. The plasma levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), thiol groups and the plasma activity of glutathione peroxidase were measured. A significant association between variant GPX3*TC+CC genotype and risk of overall testicular GCT, as well as seminoma development, was found. Moreover, carriers of variant SOD2*TT genotype were at almost 3-fold increased risk of seminoma development. Interestingly, combined SOD2*TT/GPX3*TC+CC genotype conferred a 7-fold higher risk for testicular GCT development. Finally, variant GSTM3*AC+CC genotype was associated with a higher risk for the development of advanced diseased. The presence of assessed genetic variants was not associated with significantly higher levels of redox biomarkers in both testicular GCT patients, as well as in those diagnosed with seminoma. In conclusion, the polymorphic expression of certain antioxidant enzymes might affect susceptibility toward testicular GCT development, as well as the progression of the disease.
Highlights
95% of malignant neoplasms occurring in the testis are of germ-cell origin
The question arises in terms of whether the polymorphism of the Nuclear factor-erythroid-2-related factor 2 (NRF2), GSTM3, SOD2 and GPX3 genes can affect the tumor progression, the prognosis of patients with testicular germ cell tumor (GCT) and eventually the response to systemic chemotherapy
The GPX3*TC+CC genotype was significantly associated with the risk of developing testicular GCT, including the risk of developing seminoma
Summary
95% of malignant neoplasms occurring in the testis are of germ-cell origin. Testicular germ cell tumors (GCTs) exhibiting a wide spectrum of histological patterns, pathogenetic features and clinical profiles are classified into two major entities: seminoma and non-seminoma [2,3]. A wide array of clinical determinants has been suspected of being associated with the etiopathology of testicular GCT, including components of testicular dysgenesis syndrome, encompassing cryptorchidism as the most common element [2,4]. Other hypothesized risk factors include individual genetic aberrations intensifying the susceptibility to testicular GCT, several maternal factors (dominantly referring to intrauterine exposures and surrogates), personal health-related and lifestyle characteristics (age, race, comorbidities, reproductive health issues, diet, physical activity, scrotal trauma, as well as occupational and miscellaneous exposures) and geographic and temporal determinants [5]. The assessment of genetic polymorphisms known to affect the defensive antioxidant capacity of cells, as well as detoxification processes in patients with testicular GCT, may provide a valuable contribution to this field of research
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