Reflection of p53 phenotype in tumor tissue by genotypic variants in glutathione S-transferases: An association with DNA damage in lung adenocarcinoma

Abstract

BackgroundGenetic deficiency of glutathione S-transferase (GST) results in the accumulation of tobacco carcinogens. Consequently, the elevated risk of lung carcinoma is due to increased DNA damage and p53 caretaker gene mutational frequency. ObjectiveWhether GSTM1, GSTT1 deletion, and GSTP1 Ile105Val variants genotypes are associated with the relative risk of developing p53 mutant expression and DNA damage in patients with lung adenocarcinoma. MethodsGenetic polymorphisms in GSTM1 (+/−), GSTT1 (+/−), and GSTP1 (Ile 105 Val) were identified using restriction fragment length PCR. Subsequently, the p53 phenotype was categorized as the mutant type (>50 % and ++/+++ intensity on immunohistochemistry). Lymphocytic DNA damage was assessed using a comet assay. ResultsSmoking pack-years [median (Q1-Q3); 3.5; 37.3–60.5] were associated with p53 mutant expression. Pack-years in the wild-type p53 expression group (38; 18.5–48.5, p = 0.01). The GSTM1 (−/−) null genotype was significantly associated with the risk of p53 mutant expression (RR: 1.81, p = 0.03). GSTP1 (Val/Val) also showed a significant relative risk for p53 mutant phenotype (RR: 2.23, p = 0.04). In contrast, GSTT1 was not associated with the p53 phenotype. GSTM1 (−/−)/GSTP1 (Val/Val) combined genotype showed a significant additive effect on p53 mutant phenotypic expression (RR: 4.0, p = 0.019). DNA damage was significantly associated with GSTM1 (−/−), GSTT1 (−/−) deletion genotypes, and smoking (p = 0.001, p = 0.002 and p < 0.0001, respectively). However, the p53 phenotype was not associated with DNA damage in lymphocytes. ConclusionGSTM1 (−/−) and GSTP1 (Val/Val) genotypes increased the relative risk of the p53 mutant phenotype by two-fold. GSTM1 (−/−)/GSTP1 (Val/Val) amplified the risk of the p53 mutant phenotype by four-fold. DNA damage was significantly associated with smoking, GSTM1, and GSTT1 deletions.