Association Between The XRCC1, GSTM1 And GSTT1 Polymorphisms And Thyroid Cancer Risk

1 Background and ObjectiveThyroid carcinomas are the most frequent endocrine malignancies which among these thyroid carcinomas, more than 90 percent are differentiated thyroid carcinomas(DTC). Pathologically, DTC include papillary, follicular, and Hürthle cell carcinoma. To date, exposure to ionizing radiation is the only known risk factor for thyroid cancer. However, there are evidences that some gene variants including DNA repair genes influence on DTC susceptibility. XRCC1 is one of the candidate genes which its variant relationship with thyroid cancer has not been extensively studied.The XRCC(X-Ray cross-complementing) genes were initially discovered through their role in DNA damage response caused by ionizing radiation. They are important components of various DNA repair pathways contributing to DNA-damage processing and genetic stability. X-ray cross-complementing gene 1(XRCC1) is involved in the repair of DNA base damage and singlestrand DNA breaks by binding DNA ligase III at its carboxyl and DNA polymerase β and poly(ADP-ribose) polymerase at the site of damaged DNA and is known to participate in base excision repair(BER) of small lesions such as oxidized or reduced bases, fragmented or nonbulky adducts, and lesions caused by methylating agents. Three common polymorphisms within the XRCC1 have been identified at codon 194, 280, and 399(Arg194Trp, Arg280 His, and Arg399Gln). Glutathione S transferase glycosides peptide M1(GSTM1), glutathione S transferase glycosides peptide T1(GSTT1) for phase II detoxification peptide enzyme glutathione S transferase(GST) members of the family, both have the function of detoxification of exogenous chemicals. Two individuals lack the function of genes is missing and may affect the susceptibility to cancer.Many studies have reported the association of XRCC1 Arg194 Trp, Arg280 His, Arg399 Gln, GSTM1 Null, and GSTT1 Null polymorphisms with thyroid cancer risk, but the results were inconclusive, some original studies thought that these polymorphisms were associated with thyroid cancer risk, but others had different opinions. In addition, attention has been mainly drawn at a meta-analytical level upon the association of XRCC1 Arg194 Trp, Arg280 His, Arg399 Gln, GSTM1 Null, and GSTT1 Null with thyroid cancer risk. In order to explore the association between XRCC1 Arg194 Trp, Arg280 His, Arg399 Gln, GSTM1 Null, and GSTT1 Null polymorphisms with thyroid cancer risk, an updated meta-analysis was conducted to summarize the data. Meta-analysis is a good method for summarizing the different studies. It can not only overcome the problem of small size and inadequate statistical power of genetic studies of complex traits, but also provide more reliable results than a single case–control study. 2 Materials and methods 2.1 Inclusion criteriaThe included studies needed to have met the following criteria:(1) only the case–control studies or cohort studies were considered,(2) evaluated the XRCC1 XRCC1 Arg194 Trp, Arg280 His, Arg399 Gln, GSTM1 Null, and GSTT1 Null polymorphisms and thyroid cancer risk, and(3) the genotype distribution of the polymorphisms in cases and controls were described in details and the results were expressed as odds ratio(OR) and corresponding 95% confidence interval(95% CI). Exclusion criteria(1) Not for thyroid cancer research,(2) only case population, and(3) duplicate of previous publication. Statistical analysisCrude odds ratios(ORs) together with their corresponding 95% CIs were used to assess the strength of association between the XRCC1 Arg194 Trp, Arg280 His, Arg399 Gln, GSTM1 Null, and GSTT1 Null polymorphisms and thyroid cancer risk. The pooled ORs were performed for dominant model; recessive model; Homozygote model, Heterozygote model, respectively. Heterogeneity assumption was checked by a chi-square-based Q test(Heterogeneity was considered statistically significant if P < 0.10) and quantified using the I2 value. If results were not heterogeneous, the pooled ORs were calculated by the fixed-effect model(we used the Q-statistic, which represents the magnitude of heterogeneity between-studies). Otherwise, a random-effect model was used(when the heterogeneity between-studies were significant). All of the calculations were performed using STATA version 10.0(STATA Corporation, College Station, TX). 3 ResultsThere was no significant association between these polymorphisms and thyroid cancer risk in any genetic model when all the eligible studies were pooled together. In the subgroup analysis by ethnicity, no significant association was found among Caucasians(OR = 0.87, 95% CI = 0.72–1.07, P value of heterogeneity test [Ph] = 0.127, I2 = 41.8%) and Mixed populations(OR = 0.96, 95% CI = 0.79–1.18, Ph = 0.409, I2 = 0.0%) for GSTM1 Null polymorphism. High between-studies heterogeneity was observed between GSTT1 Null polymorphism and thyroid cancer risk when all the eligble studies were pooled-into meta-analysis, Hence, They can not be pooedl-into meta-analysis together. In the subgroup analysis by ethnicity, no significant association was found among Caucasians(OR = 1.01, 95% CI = 0.78–1.31, Ph = 0.450, I2 = 0.0%) and Mixed populations(OR = 1.00, 95% CI = 0.68–1.46, Ph = 0.084, I2 = 59.7%) for GSTM1 Null polymorphism. However, in the subgroup analysis by ethnicity, the results showed that Arg/His genotype was associated with an increased risk of thyroid cancer among Caucasians(dominant model: OR = 1.43, 95% CI = 1.08–1.89, P value of heterogeneity test [Ph] = 0.513, I2 = 0.0%; additive model: OR = 1.38, 95% CI = 1.05–1.80, Ph = 0.551, I2 = 0.0%; Heterozygote model: OR = 1.45, 95% CI = 1.09–1.93, Ph = 0.495, I2 = 0.0%). And carriers of the 399 Gln variant allele have a decreased thyroid cancer risk in mixed population(dominant model: OR = 0.73, 95% CI = 0.55–0.97, Ph = 0.326, I2 = 0.0%; additive model: OR = 0.73, 95% CI = 0.59–0.92, Ph = 0.308, I2 = 3.6%; recessive model: OR = 0.56, 95% CI = 0.34–0.93, Ph = 0.588, I2 = 0.0%; homozygote model: OR = 0.50, 95% CI = 0.30–0.85, Ph = 0.460, I2 = 0.0%). We also detected that the Trp allele of Arg194 Trp polymorphism was significantly increased thyroid cancer risk in mixed population(additive model: OR = 1.49, 95% CI = 1.02–2.17). When subgroup analysis by histological subtype, the results showed that Arg194 Trp polymorphism was associated with decreased papillary thyroid cancer(PTC) risk in dominant model(OR = 0.71, 95% CI = 0.50–0.99, Ph = 0.525, I2 = 0.0%). However, when the study of Ho et al. was excluded, the results were changed in mixed population for Arg399Gln(dominant model: OR = 1.06, 95% CI = 0.47–2.40; additive model: OR = 1.00, 95% CI = 0.53–1.88; recessive model: OR = 0.82, 95% CI = 0.19–3.55; homozygote model: OR = 0.86, 95% CI = 0.19–3.92). For Arg194 Trp polymorphism, when one study was excluded, the results were also changed in mixed population(data not shown) and PTC(dominant model: OR = 0.85, 95% CI = 0.55–1.29). For Arg280 His polymorphism, when one study was excluded, the results were also changed in Caucasians(dominant model: OR = 1.25, 95% CI = 0.84–1.85; additive model: OR = 1.21, 95% CI = 0.83–1.76; Heterozygote model: OR = 1.28, 95% CI = 0.86–1.90). 4 ConclusionsIn summary, this meta-analysis indicates that XRCC1 Arg194 Trp, Arg280 His, Arg399 Gln, GSTM1 Null, and GSTT1 Null may be not associated with thyroid cancer risk.