The Association Between Acute Lymphoblastic Leukemia And Glutathione-S-transferase Genes And Its Clinical Significance: A Meta-analysis

Background Acute lymphoblastic leukemia(ALL)is a kind of malignant neoplastic disease in which B-cells or T-cells originating from lymphocytes proliferate abnormally in the bone marrow.Although our understanding of the disease has evolved over the past few decades,the role of different types of molecular targets in the diagnosis、treatment、development and prognosis of the disease is not fully understood.Through clinical gene sequencing and combined with related research,we found that the damage of hematopoietic progenitor cell is the foundation of the etiology.There are many ways to prevent and repair the DNA damage in our body,and detoxifying enzymes play an important role in it.Phase I enzymes can convert hazardous substances to precarcinogen,and then under the action of phase II enzymes,turning it into non-toxic material.Finally the transporters remove them from the cells,and passed them out of the body in the urine.Glutathione S-transferase(GST)are phase II enzymes involved in metabolism and detoxification of xenobiotics and carcinogens.Many published studies focused on GSTM1,GSTT1 and GSTP1 genetic mutant types with respect to the susceptibility to acute lymphoblastic leukemia(ALL).However,the results of these studies have shown inconsistency.The purpose of this study is to conduct a comprehensive and systematic meta-analysis to obtain a precise and accurate evaluation of the relationship of them,because we believe that it can not only help us get a better understanding on its pathogenesis but also provide potential molecular targets so as to guide the diagnosis、prevention and follow-up of the disease.Methods A systematic literature search was performed through Pub Med、Medline、Cochrane、CBM and the Wan Fang databases to acquire all eligible studies.Odds ratios and 95% confidence intervals were calculated.Data were extracted and study quality was examined by the Newcastle-Ottawa scale.Sub-group analyses were performed on age,ethnicity,region,quality,source of control,and the Hardy–Weinberg equilibrium.Publication bias was evaluated and further examined by the trim and fill algorithm.Results Following a systematic literature search in the databases on the relevance between GST polymorphisms and ALL susceptibility,47 publications containing 104 independent case-control studies(GSTM1,44;GSTT1,40;GSTP1,20)with a total of 12,642 cases(GSTM1,5410;GSTT1,4938;GSTP1,2294)and 20459 controls(GSTM1,8653;GSTT1,8023;GSTP1,3783)were finally enrolled in this meta-analysis.A positive susceptibility to ALL was discovered in patients with null-type GSTM1(OR=1.352,95%CI=1.200-1.524,P<0.001),GSTT1(OR=1.374,95%CI= 1.168-1.618,P<0.001)and GSTP1(OR=1.225,95%CI=1.054-1.424,P<0.05),but with evidence of heterogeneity.To explore the sources of heterogeneity,subgroup analyses was used.Publication bias was identified on GSTM1 analysis,and no significant publication bias was identified for GSTT1 and GSTP1 gene models in this meta-analysis.Therefore,a trim and fill method was adopted to evaluate the influence caused by possible publication bias.No significant change was observed in the trim and fill process(Original: log OR=0.302,CI=0.183-0.421,P<0.01;Filled: log OR=0.146,CI=0.018-0.274,P<0.05),indicating the stability of our results.Conclusions GSTM1 and GSTT1 polymorphisms contribute to both childhood and adult ALL susceptibility while GSTP1 polymorphism was only positively related to pediatric ALL.The Asian and Caucasian populations were found to be more susceptible to ALL.