GSTT1 Null Genotype Significantly Increases the Susceptibility to Urinary System Cancer: Evidences from 63,876 Subjects

Abstract

GSTT1 gene plays an important role in detoxification and clearance of reactive oxygen species(ROS). A null variant in this gene has been demonstrated to confer cancer susceptibility. Although many studies have demonstrated the association between GSTT1 null polymorphism and urinary system cancer susceptibility, several publications reported opposite conclusions. For better understanding the effects of this polymorphism on the risk of urinary system cancer, a updated meta-analysis was performed with a total of 26,666 cases and 37,210 controls extracted from 117 studies, by following the latest meta-analysis guidelines (PRISMA). The results suggested that the GSTT1 null genotype was significantly associated with an increased risk of urinary system cancer (OR=1.13, 95%CI=1.05-1.22). Furthermore, stratified analyses by the type of cancer, ethnicity, source of control and quality score presented a significantly increased risk associated with GSTT1 null genotype in bladder and prostate cancer subgroup, Caucasians and Indians subgroup, population-based(PB) subgroup, medium quality and low quality subgroup. Overall, our meta-analysis suggested that GSTT1 null genotype is a potential cancer susceptibility variant. Well-designed and large-cohort studies are needed to confirm the association between GSTT1 null genotype and urinary system cancer risk.

Keywords: GSTT1; meta-analysis; oxidative stress; polymorphism; susceptibility; urinary system cancer.

Fig 1

Schematic of the potential roles of GSTT1 in preventing cells from tumorigenesis. GSTT1 prevent cells from tumorigenesis via promoting p38/MK2 mediated apoptosis and senescence. High thiol levels and the absence of oxidative stress keep the GSTT1 in monomeric form. (A) Monomeric GSTT1 dissociates from p38 and MK2, and binds to its inhibitor. (B) In the presence of pro-oxidative stimuli, dimerized GSTT1 binds to p38 and MK2, promoting the activity of these kinases, which in turn elevate the expression of GSTT1. (C) After interacting with MKK3, Phosphorylated p38 and MK2 initiate the reduction of polarization of mitochondrial membrane potential, which activates apoptosis and senescence. Abbreviations: GSTT1, glutathione S‑transferase theta 1; MK2, mitogen-activated protein kinase-activated protein kinase 2; MKK3, mitogen-activated protein kinase 3.

Fig 2

Flowchart of included studies for the meta-analysis of the association between GSTT1 null genotype and urinary system cancer risk.

Fig 3

Forest plot of the association between GSTT1 null genotype and urinary system cancer risk. For each study, the estimates of ORs and corresponding 95% CI are plotted with a box and a horizontal line. Diamond, pooled ORs and its 95% CI.

Fig 4

Forest plot of the association between GSTT1 null genotype and urinary system cancer risk which is straitified by the type of cancer. For each study, the estimates of ORs and corresponding 95% CI are plotted with a box and a horizontal line. Diamond, pooled ORs and its 95% CI.

Fig 5

Sensitivity analysis of the association between GSTT1 null genotype and urinary system cancer risk. Each point represents the recalculated OR after deleting a separate study.

Fig 6

Funnel plot analysis to detect the publication bias for GSTT1 null genotype and urinary system cancer risk. Each point represents a separate study. Funnel plot of the Begg's test for (A) 117 studies, Z=3.03, P=0.002; and (B) for 98 studies after dropping 19 studies with low quality, Z=1.94, P=0.052.