Impact of SNP-SNP interactions of DNA repair gene ERCC5 and metabolic gene GSTP1 on gastric cancer/atrophic gastritis risk in a Chinese population.
ABSTRACT: To investigate the interactions of the DNA repair gene excision repair cross complementing group 5 (ERCC5) and the metabolic gene glutathione S-transferase pi 1 (GSTP1) and their effects on atrophic gastritis (AG) and gastric cancer (GC) risk.Seven ERCC5 single nucleotide polymorphisms (SNPs) (rs1047768, rs2094258, rs2228959, rs4150291, rs4150383, rs751402, and rs873601) and GSTP1 SNP rs1695 were detected using the Sequenom MassARRAY platform in 450 GC patients, 634 AG cases, and 621 healthy control subjects in a Chinese population.Two pairwise combinations (ERCC5 rs2094258 and rs873601 with GSTP1 rs1695) influenced AG risk (Pinteraction = 0.008 and 0.043, respectively), and the ERCC5 rs2094258-GSTP1 rs1695 SNP pair demonstrated an antagonistic effect, while ERCC5 rs873601-GSTP1 rs1695 showed a synergistic effect on AG risk OR = 0.51 and 1.79, respectively). No pairwise combinations were observed in relation to GC risk. There were no cumulative effects among the pairwise interactions (ERCC5 rs2094258 and rs873601 with GSTP1 rs1695) on AG susceptibility (Ptrend > 0.05). When the modification effect of Helicobacter pylori (H. pylori) infection was evaluated, the cumulative effect of one of the aforementioned pairwise interactions (ERCC5 rs873601-GSTP1 rs1695) was associated with an increased AG risk in the case of negative H. pylori status (Ptrend = 0.043).There is a multifarious interaction between the DNA repair gene ERCC5 SNPs (rs2094258 and rs873601) and the metabolic gene GSTP1 rs1695, which may form the basis for various inter-individual susceptibilities to AG.
Project description:We conducted a case-control study to evaluate the association between ERCC5 polymorphism and breast cancer risk. 325 breast cancer patients and 325 controls were recruited in our study between January 2011 and March 2014. ERCC5 rs1047768, rs2094258, rs2296147, rs751402 and rs873601 polymorphisms were genotyped, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. By logistic regression analysis, we found that individuals with AA genotype of rs2094258 was associated with increased risk of breast cancer when compared with wide-type genotype, and the OR (95% CI) was 1.80 (1.12-2.92) for AA genotype. Individuals with GA+GG genotype of rs2094258 were significantly correlated with increased risk of breast cancer in tobacco smokers, and the OR (95% CI) was 7.35 (1.21-47.20). In conclusion, our study indicated that ERCC5 rs2094258 polymorphism may contribute to the risk of breast cancer.
Project description:BACKGROUND:Adjuvant chemotherapy in patients with resected esophageal squamous cell cancer (ESCC) remains controversial for its uncertain role in improving overall survival (OS). Nucleotide excision repair (NER) removes DNA-adducts in tumor cells induced by the platinum-based chemotherapy and thus may modulate efficacy of the treatment. The present study evaluated if single nucleotide polymorphisms (SNPs) of NER genes were prognostic biomarkers in ESCC patients treated with platinum-based adjuvant chemotherapy (PAC). METHODS:The analysis included 572 patients, for whom six SNPs of NER genes [i.e., XPC (rs1870134 and rs2228001), ERCC2/XPD rs238406 and ERCC5/XPG (rs2094258, rs2296147 and rs873601)] were detected with the TaqMan assay. Kaplan-Meier analyses and Cox proportional hazards models were used to evaluate their associations with disease free survival (DFS) and OS of these ESCC patients receiving PAC. Receiving operating characteristic curve analysis was used to evaluate the role of the risk genotypes in the DFS and OS. RESULTS:We found that ERCC5/XPG rs2094258 and rs873601 and ERCC2/XPD rs238406 SNPs were independently associated with poorer DFS and OS of ESCC patients [ERCC5/XPG rs2094258: CT+TT vs. CC: adjusted hazards ratio (adjHR) = 1.68 and P = 0.012 for DFS; adjHR = 1.99 and P = 0.0001 for OS; ERCC5/XPG rs873601: GA+GG vs. AA: adjHR = 1.59 and P = 0.024 for DFS; adjHR = 1.91 and P = 0.0005 for OS; ERCC2/XPD rs238406: TT vs. GG+GT: adjHR = 1.43 and P = 0.020 for DFS; adjHR = 1.52 and P = 0.008 for OS]. These HRs increased as the number of risk genotypes increased in the combined analysis. The model combining the risk genotypes with clinical characteristics or the TNM stage system was better in predicting outcomes in ESCC patients with PAC. CONCLUSION:SNPs of ERCC2/XPD and ERCC5/XPG may independently and jointly predict survival of ESCC patients treated with PAC in this study population. Further validation in other study populations is warranted.
Project description:Nucleotide excision repair (NER) is a versatile system that repairs various DNA damage. Polymorphisms of core NER genes could change NER ability and affect gastric cancer (GC) prognosis. We systematically analyzed the association between 43 SNPs of ten key NER pathway genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, ERCC8, XPA, XPC, and DDB2) and overall survival (OS) of 373 GC patients in Chinese. Genotyping was performed by Sequenom MassARRAY platform. We found for the first time that carriers of ERCC2 rs50871 GG genotype demonstrated significantly increased hazards of death than GT/TT individuals (HR=2.55, P=0.002); ERCC6 rs1917799 heterozygote GT were associated with significantly shorter OS than wild-type TT (adjusted HR=1.68, P=0.048); patients with DDB2 rs3781619 GG genotype suffered higher hazards of death compared with AG/AA carriers (adjusted HR=2.30, P=0.003). Patients with ERCC1 rs3212961 AA/AC genotype exhibited longer OS than CC genotype (adjusted HR=0.63, P=0.028); ERCC5 rs2094258 AA/AG genotype revealed significantly favorable OS compared with GG genotype (adjusted HR=0.65, P=0.033); DDB2 rs830083 CG genotype could increase OS compared with GG genotype (adjusted HR=0.61, P=0.042). Furthermore, patients simultaneously carrying two "hazard" genotypes exhibited even significantly worse survival with HR of 3.75, 3.76 and 6.30, respectively. Similarly, combination of "favorable" genotypes predicted better prognosis with HR of 0.56, 0.49 and 0.33, respectively. In conclusion, ERCC2 rs50871 G/T, ERCC6 rs1917799 G/T, DDB2 rs3781619 A/G polymorphisms could predict shorter OS while ERCC1 rs3212961 A/C, ERCC5 rs2094258 A/G, DDB2 rs830083 C/G polymorphisms could predict longer OS of GC, which might serve as promising biomarkers for GC prognosis.
Project description:Gastric cancer (GC) is a multistep complex disease involving multiple genes, and gene-gene interactions have a greater effect than a single gene in determining cancer susceptibility. This study aimed to explore the interaction of the let-7e rs8111742, miR-365b rs121224, and miR-4795 rs1002765 single nucleotide polymorphisms (SNPs) with SNPs of the predicted target gene PGC and Helicobacter pylori status in GC and atrophic gastritis (AG) risk. Three miRNA SNPs and seven PGC SNPs were detected in 2448 cases using the Sequenom MassArray platform. Two pairwise combinations of miRNA and PGC SNPs were associated with increased AG risk (let-7e rs8111742 - PGC rs6458238 and miR-4795 rs1002765 - PGC rs9471643). Singly, miR-365b rs121224 and PGC rs6912200 had no effect individually but in combination they demonstrated an epistatic interaction associated with AG risk. Similarly, let-7e rs8111742 and miR-4795 rs1002765 SNPs interacted with H. pylori infection to increase GC risk (rs8111742: Pinteraction = 0.024; rs1002765: Pinteraction = 0.031, respectively). A three-dimensional interaction analysis found miR-4795 rs1002765, PGC rs9471643, and H. pylori infection positively interacted to increase AG risk (Pinteraction = 0.027). Also, let-7e rs8111742, PGC rs6458238, and H. pylori infection positively interacted to increase GC risk (Pinteraction = 0.036). Furthermore, both of these three-dimensional interactions had a dosage-effect correspondence (Ptrend < 0.001) and were verified by MDR. In conclusion, the miRNAs SNPs (let-7e rs8111742 and miR-4795 rs1002765) might have more superior efficiency when combined with PGC SNPs and/or H. pylori for GC or AG risk than a single SNP on its own.
Project description:BACKGROUND:The xeroderma pigmentosum group G (XPG) gene at chromosome 13q33 consists of 15 exons, which may be related to the occurrence and development of gastric cancer (GC). AIM:To examine the association of several common single nucleotide polymorphisms (SNPs) of the XPG gene with GC risk and survival. METHODS:Five SNPs of XPG (rs2094258, rs751402, rs873601, rs2296147, and rs1047768) were genotyped by PCR restriction fragment length polymorphism in 956 histologically confirmed GC cases and 1012 controls in North China. GC patients were followed for survival status and, if deceased, cause of death. Logistic regression and Cox regression were used for analysing associations of XPG SNPs with risk of GC and prognosis, respectively. For rs2094258, heterozygous model (CT vs CC), homozygous model (TT vs CC), recessive model (TT vs CT + CC), and dominant model (TT + CT vs CC) were analyzed. RESULTS:None of the examined loci were statistically associated with GC risk, although rs2296147 was marginally associated with GC risk (P = 0.050). GC patients with the rs2094258 CT + CC genotype showed worse survival than those with the TT genotype (log-rank test, P = 0.028), and patients with the CC genotype had a tendency of unfavourable prognosis compared with those with the TT + CT genotype (log-rank test, P = 0.039). The increase in C alleles of rs2094258 [hazard ratio (HR) = 1.19, 95% confidence interval (CI): 1.02-1.45, P = 0.037] were associated with the long-term survival of GC cases. Other risk factors for survival included tumor differentiation (HR = 4.51, 95%CI: 1.99-8.23, P < 0.001), lymphovascular invasion (HR = 1.97, 95%CI: 1.44-3.01, P < 0.001), and use of chemotherapy (HR = 0.81, 95%CI: 0.63-0.98, P = 0.041). CONCLUSION:The XPG rs2094258 polymorphism may be associated with overall survival in GC patients.
Project description:BACKGROUND Gene polymorphisms are associated with sensitivity to platinum drugs. This study aimed to investigate the polymorphisms of GSTP1 rs1695 locus and ABCC2 rs717620 locus, and the sensitivity of patients with advanced non-small cell lung cancer (NSCLC) to platinum drugs in a Xinjiang Uygur population. MATERIAL AND METHODS The gene polymorphisms of GSTP1 rs1695 and ABCC2 rs717620 of Uygur NSCLC patients were assessed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The relationship between the prognosis of advanced NSCLC Uygur patients and the gene polymorphisms of GSTP1 rs1695 and ABCC2 rs717620 was analyzed using progression-free survival (PFS) and overall survival (OS) as the major outcome indicators. RESULTS The median PFS of patients with advanced NSCLC was 6.9 months and the OS of Uygur patients with advanced NSCLC was 10.8 months. Kaplan-Meier survival analysis indicated that survival time of patients with GSTP1 AG + GG was significantly longer than in patients with AA gene (P<0.05), and survival time of patients with ABCC2 CT + TT was significantly longer than in patients with the CC gene (P<0.05). CONCLUSIONS Polymorphisms of GSTP1 rs1695 and ABCC2 rs717620 can be used to predict the outcomes of Uygur patients with advanced NSCLC who have received platinum-based chemotherapy. Additionally, this information could be used to guide the individualized treatment of Uygur patients with advanced NSCLC.
Project description:Previous studies have reported that xeroderma pigmentosum group G (XPG) gene polymorphisms may modulate colorectal cancer (CRC) susceptibility. In this study, we performed a two-stage case-control study to comprehensively investigate the associations of five polymorphisms in the XPG gene with CRC risk in 1,901 cases and 1,976 controls from Southern China, including rs2094258 C>T, rs751402 C>T, rs2296147 T>C, rs1047768 T>C and rs873601 G>A. After combining data from two stages, we found that three of the studied polymorphisms (rs2094258 C>T, rs751402 C>T, and rs873601 G>A) were significantly associated with CRC susceptibility. After adjustment for age and gender, multivariate logistic regression analysis indicated that carriers of the rs2094258 T alleles had an increased CRC risk [CT vs. CC: adjusted odds ratio (OR)=1.17, 95% confidence interval (CI)=1.01-1.36; TT vs. CC: adjusted OR=1.49, 95% CI=1.18-1.89; TT vs. CT/CC: adjusted OR=1.38, 95% CI=1.10-1.72]. Likely, rs873601 A allele also conferred increased CRC susceptibility. In contrast, a protective association was identified between rs751402 C>T polymorphism and the risk of CRC. In summary, our results indicated that these three polymorphisms were found to associate with CRC susceptibility in a Southern Chinese population.
Project description:OBJECTIVE:Polymorphisms in XPG were considered to contribute to the clinical outcome of patients receiving platinum drug chemotherapy. We investigated the impact of several potential SNPs of XPG on the efficacy of platinum-based chemotherapy in NSCLC patients. METHODS:A total of 433 patients were consecutively selected between Nov. 2006 and Dec. 2007, and were followed-up up to Nov. 2011. The genotyping of six SNPs (rs2296147, rs751402, rs873601, rs4150375, rs17655 and rs2094258) were genotyped using the Taqman real-time PCR method with a 7900 HT sequence detector system. RESULTS:Patients carrying CT+TT genotype of rs2296147 had a significantly longer median PFS (17.5 months) and OS (26.8 months) than CC genotype. Hazard ratio (HR) for PFS and OS in patients with CT+TT genotype of rs2296147 was respectively 0.73(0.51-0.97) and 0.66(0.48-0.99) when compare CC genotype, respectively. Similarly, patients with rs2094258 AG+GG genotype had a longer median progression time (18.4 months) and overall survival time (27.3 months) when compared with those with AA genotype, and HRs(95% CI) for PFS and OS were 0.44(0.34-0.78) and 0.51(0.39-0.82), respectively. CONCLUSIONS:Our study suggests rs2296147 CT+TT and rs2094258 AG+GG genotypes contribute to the better survival of NSCLC. Our study provides significant information on role of prognostic value of XPG SNPs, and detecting of XPG could be used as predictive markers toward individualizing NSCLC treatment strategies.
Project description:Background Response to glucocorticoid (GC) monotherapy in the initial phase of remission induction treatment in childhood acute lymphoblastic leukemia (ALL) represents important biomarker of prognosis and outcome. We aimed to study variants in several pharmacogenes (NR3C1, GSTs and ABCB1) that could contribute to improvement of GC response through personalization of GC therapy. Methods Retrospective study enrolling 122 ALL patients was carried out to analyze variants of NR3C1 (rs33389, rs33388 and rs6198), GSTT1 (null genotype), GSTM1 (null genotype), GSTP1 (rs1695 and rs1138272) and ABCB1 (rs1128503, rs2032582 and rs1045642) genes using PCR-based methodology. The marker of GC response was blast count per microliter of peripheral blood on treatment day 8. We carried out analysis in which cut-off value for GC response was 1000 (according to Berlin-Frankfurt-Munster [BFM] protocol), as well as 100 or 0 blasts per microliter. Results Carriers of rare NR3C1 rs6198 GG genotype were more likely to have blast count over 1000, than the non-carriers (p = 0.030). NR3C1 CAA (rs33389-rs33388-rs6198) haplotype was associated with blast number below 1000 (p = 0.030). GSTP1 GC haplotype carriers were more likely to have blast number below 1000 (p = 0.036), below 100 (p = 0.028) and to be blast negative (p = 0.054), while GSTP1 GT haplotype and rs1138272 T allele carriers were more likely to be blasts positive (p = 0.034 and p = 0.024, respectively). ABCB1 CGT (rs1128503-rs2032582-rs1045642) haplotype carriers were more likely to be blast positive (p = 0.018). Conclusions Our results have shown that NR3C1 rs6198 variant and GSTP1 rs1695-rs1138272 haplotype are the most promising pharmacogenomic markers of GC response in ALL patients.
Project description:SNPs may restrict cell detoxification activity and be a potential risk factor for cancer chemosensitivity. We evaluated the predictive value of these polymorphisms on the sensitivity of bladder cancer patients to epirubicin and mitomycin chemotherapy instillation as well as their toxicities. SNPs were analyzed by TaqMan genotyping assays in 130 patients treated with epirubicin and 114 patients treated with mitomycin. Recurrence-free survival (RFS) was estimated by the Kaplan-Meier method, and hazard ratios (HRs) and 95% confidence intervals (CIs) of the HRs were derived from multivariate Cox proportional hazard models. GSTP1 rs1695 and GSTO1 rs4925 were also associated with RFS in the epirubicin group. Patients carrying the GSTP1 AG+GG and GSTO1 AC+AA genotypes had an unfavorable RFS. Patients with the GSTP1 AA and GSTO1 CC genotypes had a reduced risk of recurrence after the instillation of epirubicin. In addition, patients with the GSTP1 rs1695 AA genotype had an increased risk of irritative voiding symptoms; while patients with the GSTO1 rs4925 CC genotype had a decreased risk of hematuria. Our results suggest that GSTP1 and GSTO1 polymorphisms are associated with epirubicin treatment outcomes as well as with epirubicin-related toxicity.