Association of GSTP1 and XRCC1 gene polymorphisms with clinical outcome of advanced non-small cell lung cancer patients with cisplatin-based chemotherapy

We investigated the association between the clinical outcome and GSTP1 and XRCC1 gene polymorphisms in advanced NSCLC patients with cisplatin-based chemotherapy. We prospectively recruited 325 NSCLC patients between January 2010 and January 2014. Genotypes of GSTP1 A313G, XRCC1 Arg194Trp, Arg280His and Arg399Gln were conducted using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. AG and GG genotypes of GSTP1 A313G were correlated with a higher CR + PR when compared with AA genotype. Furthermore, GA and AA genotypes of XRCC1 Arg399Gln were associated with more CR + PR when compared with GG genotype. In the Cox proportional hazards model, GG genotype of GSTP1 A313G was significantly correlated with a longer median survival time when compared with AA genotype, and it is associated with a heavy decreased risk of death from NSCLC. Moreover, GA and AA genotypes of XRCC1 Arg399Gln had a significantly longer median survival time, and GA and AA genotypes were significantly associated with a moderate reduced risk of death from NSCLC. GSTP1 A313G and XRCC1 Arg399Gln gene polymorphisms might influence the response to cisplatin-based chemotherapy and affect the clinical outcome of advanced NSCLC.     

Association of GSTs polymorphisms with risk of gestational diabetes mellitus

We conducted a case-control study to investigate the association between GSTM1, GSTT1 and GSTP1 IIe105Val polymorphisms and development of gestational diabetes mellitus in a Chinese population. A total of 320 patients with gestational diabetes mellitus and 358 pregnancy subjects were consecutively collected between January 2013 and December 2014. Genotyping for detection of GSTM1, GSTT1 and GSTP1 IIe105Val was conducted by using PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphisms) method. By Fisher’s exact test, we found that the genotype distributions of GSTP1 IIe105Val were in line with the Hardy-Weinberg equilibrium in control subjects (P=0.57). By Chi-square test, we found significant differences in the genotype distributions of GSTM1 (χ²=11.49, P=0.001) and GSTT1 (χ²=18.50, P<0.001). Using unconditional logistic analysis, individuals carrying the null genotypes of GSTM1 and GSTT1 were associated with an increased risk of gestational diabetes mellitus when compared with the present genotype, and the adjusted Ors (95% CI) were 1.71 (1.24-2.36) and 2.00 (1.44-2.79), respectively. However, the GSTP1 IIe105Val polymorphism was not associated with an elevated risk of gestational diabetes mellitus. In conclusion, we suggest that the GSTM1 null genotype and GSTT1 null genotype are correlated with an increased risk of gestational diabetes mellitus in a Chinese population.     

Cardiotoxicity of cisplatin-based chemotherapy in advanced non-small cell lung cancer patients

Cardiotoxicity is a well known consequence of cancer chemotherapy. Cisplatin-based combinations are standard regimens in the therapy of advanced non-small cell lung cancer. Administration of cisplatin-containing chemotherapy causes significant oxidative and nitrosative stress in some patients. Cardiac blood biomarkers can be used to evaluate cardiac status, may help to identify patients at risk myocardial damage evaluation and are able to detect subclinical, early-stage cisplatin-induced cardiotoxicity. The relevance of cardiovascular complications in cancer patients and identification of individual risk factors for developing cardiovascular toxicity merit further evaluation and a longer follow-up is needed.     

壮族人群少精不育患者精细胞GSTT1和GSTM1基因研究

目的:探讨壮族人群精细胞GSTT1和GSTM1基因多态性与少精症的关系。方法:应用PCR法对75名壮族少精不育患者及36名健康男性精细胞GSTT1和GSTM1基因进行多态性研究,探讨该基因对少精症的影响。结果:实验组GSTM1基因及GSTM1+GSTT1组合的缺失型基因高于对照组,差异有统计学意义(P0.05)。结论:壮族人群精细胞GSTM1基因和GSTT1+GSTM1基因多态性与男性少精症有着较为密切的联系,其具体作用机制有待进一步研究。     

Polymorphisms of the genes encoding the GSTM1, GSTT1 and GSTP1 in Korean women: no association with endometriosis

Endometriosis, one of the most common gynaecologic disorders, shows significantly elevated prevalence in industrial areas and there is also a possible genetic predisposition. Glutathione-S-transferases (GSTs) are enzymes involved in the metabolism of many disease-causing carcinogens and mutagens that are present in human environments. An association between the incidence of endometriosis and the GST genotypes of patients has been suggested. The objective of the present study was to investigate whether the polymorphisms of GSTM1, GSTT1 and GSTP1 are related to endometriosis. Blood samples were available from 259 controls and 194 patients with advanced endometriosis diagnosed by both pathology and laparoscopic findings. The proportion of the GSTM1, GSTT1 and GSTP1 genotypes of the control group were comparable to other populations. There was no significant evidence that the distribution of the GSTM1 and GSTT1 genotype differed between the patients and the controls, with an allelic odds ratio (OR)=1.074 [95% confidence interval (CI)=0.737-1.564] and 1.239 (95% CI = 0.853-1.799), respectively. Also, there was no significant difference in the proportion of GSTP1 genotypes between the women with endometriosis and the control group with the OR = 0.823 (95% CI = 0.536-1.264). The higher risk alleles were contended as GSTM1, GSTT1 null mutation and GSTP1 Ile105Ile polymorphism. There was no significant increase in the risk of endometriosis as the number of higher risk alleles of the GST family increased. In conclusion, our findings suggest that the GSTM1, GSTT1 and GSTP1 genetic polymorphisms are not associated with the development of endometriosis in Korean women.     

Assoication of XRCC1 gene polymorphisms with risk of non-small cell lung cancer

DNA repair genes is a key factor for cancer susceptibility, and we conducted a case-control study to investigate the association of XRCC1 codons 194 (Arg to Trp), 280 (Arg to His) and 399 (Arg to Gln) with risk of NSCLC. 210 NSCLC patients and 210 health control subjects were randomly selected from Huaihe Hospital between January 2012 and June 2014. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was taken to assess the genotyping of XRCC1 Arg194Trp, Arg280His and Arg399Gln. By multivariate logistic regression analysis, we found individuals carrying with Trp/Trp and Arg/Trp + Trp/Trp genotypes were associated with a significantly increased risk of NSCLC compared with Arg/Arg genotype, and the OR (95% CI) were 3.15 (1.32-8.09) and 1.52 (1.02-2.28), respectively. The potential association of Arg/Trp+ Trp/Trp genotype of XRCC1 Arg194Trp with the risk of NSCLC is more evidence in smokers, and the OR (95% CI) was 1.78 (1.01-3.24). In conclusion, we found that XRCC1 Arg194Trp polymorphism may be associated with NSCLC risk, especially in smokers.     

Possible risk modification by CYP1A1, GSTM1 and GSTT1 gene polymorphisms in lung cancer susceptibility in a South Indian population

Susceptibility to lung cancer has been shown to be modulated by inheritance of polymorphic genes encoding cytochrome P450 1A1 (CYP1A1) and glutathione S transferases (GSTM1 and GSTT1), which are involved in the bioactivation and detoxification of environmental toxins. As the incidence of lung cancer is known to differ according to ethnicity, we have conducted a case-control study of 146 South Indian lung cancer patients along with 146 healthy controls, to assess any association between CYP1A1, GSTM1 and GSTT1 polymorphisms, either separately or in combination, with the likelihood of development of lung cancer in our population. The current weight of evidence from our study indicated that the frequency of CYP1A1 MspI homozygous variant alleles was significantly higher in cases (OR=3.178). We observed a considerable difference in the GSTT1 null deletion frequency in this population when compared with other populations (OR=2.472, 95% CI: 1.191–5.094, P=0.014). There was no relative risk in GSTM1 null genotype when analysed singly (P=0.453). Considering genotype combinations, risk of lung cancer increased remarkably significantly in individuals having one variant allele of CYP1A1, GSTM1, or GSTT1, suggesting gene–gene interactions. Rare genotypic combinations (such as CYP1A1 wild GSTM1 or GSTT1 either null; CYP1A1 variant both GSTM1 and GSTT1 present; CYP1A1 variant GSTM1 or GSTT1 either null), were at higher risk compared to the reference group. Moreover, patients who had smoked <20 pack years and harboured the CYP1A1 variant allele or the GSTT1 null genotype also had a significant risk of lung cancer. Hence our study—the first to analyse a South Indian population—suggests the importance of combined CYP1A1, GSTM1 and GSTT1 polymorphisms in the development of smoking-induced lung cancer.     

贝伐单抗联合化学药物治疗耐药晚期非小细胞肺癌

目的：探讨贝伐单抗联合化学药物治疗耐药晚期非小细胞肺癌（non—smallcelllung ca11cer,NSCLC）的疗效及安全性。方法：对2011年1月至2012年9月收治的9例耐药晚期NSCLC患者给予贝伐单抗联合化疗治疗,其中多西他赛联合贝伐单抗3例、培美曲塞二钠联合贝伐单抗5例、紫杉醇联合贝伐单抗1例。每例患者均完成2个周期以上治疗,观察其近期疗效及安全性。结果：9例患者中,3例部分缓解。无进展生存期2～12个月,总生存期4～16个月。主要不良反应有骨髓抑制、下肢静脉血栓、充血性心力衰竭、血压升高、消化道反应以及脱发。结论：贝伐单抗联合化疗治疗耐药晚期NSCLC取得较好疗效,毒性可以耐受。     

Association between COX-2 polymorphisms and non-small cell lung cancer susceptibility

Aim: To explore the association between COX-2 polymorphisms and non-small cell lung cancer (NSCLC) susceptibility. Methods: We collected fasting peripheral venous blood from 60 cases with NSCLC and 62 healthy controls through physical examinations, and applied PCR-RFLP to analyze COX-2 polymorphisms of two groups. Results: With respect to detecting COX-2 rs689466 and rs5275 polymorphisms, the distribution frequency of mutant genotype AA of COX-2 rs689466 in case group was higher than that in control group, which possessed significant difference between two groups (P < 0.05). Carriers with AA genotype were 4.05 times at risk of NSCLC than those with GG genotype (P = 0.04, OR=4.05, 95% CI = 1.14-14.43). The distribution of mutant genotype CC of COX-2 rs5275 was different between two groups, and carriers with genotype CC were at 5.70 times higher risk of NSCLC than those with genotype TT. After corrected by sex, gender, smoking and drinking factors, AA genotype of COX-2 rs689466 and CC genotype of COX-2 rs5275 still contributed to increased risk of NSCLC (OR=4.22, 95% CI=1.10-16.17, OR=6.95, 95% CI=1.27-38.11). After analyzed of linkage disequilibrium (LD) and haplotypes of alleles in two SNPs, the distribution frequency of A-C haplotype in case group was higher than that in control group, with significant difference between two groups (P < 0.05). After corrected by sex, gender, smoking and drinking factors, statistical difference was still found in the total distribution of A-C haplotype between two groups (P = 0.03, OR=6.11, 95% CI=1.16-32.2). Conclusions: COX-2 rs689466 and rs5275 polymorphisms may be related to NSCLC susceptibility. And A-C haplotype might be a susceptibility haplotype for NSCLC.     

Prognostic assessment of apoptotic gene polymorphisms in non-small cell lung cancer in Chinese

Apoptosis plays a key role in inhibiting tumor growth, progression and resistance to anti-tumor therapy. We hypothesized that genetic variants in apoptotic genes may affect the prognosis of lung cancer. To test this hypothesis, we selected 38 potentially functional single nucleotide polymorphisms (SNPs) from 12 genes (BAX, BCL2, BID, CASP3, CASP6, CASP7, CASP8, CASP9, CASP10, FAS, FASLG and MCL1) involved in apoptosis to assess their prognostic significance in lung cancer in a Chinese case cohort with 568 non-small cell lung cancer (NSCLC) patients. Thirty-five SNPs passing quality control underwent association analyses, 11 of which were shown to be significantly associated with NSCLC survival (P < 0.05). After Cox stepwise regression analyses, 3 SNPs were independently associated with the outcome of NSCLC (BID rs8190315: P = 0.003; CASP9 rs4645981: P = 0.007 and FAS rs1800682: P = 0.016). A favorable survival of NSCLC was significantly associated with the genotypes of BID rs8190315 AG/GG (adjusted HR = 0.65, 95% CI: 0.49-0.88), CASP9 rs4645981 AA (HR = 0.22, 95% CI: 0.07-0.69) and FAS rs1800682 GG (adjusted HR = 0.67, 95% CI: 0.46-0.97). Time-dependent receptor operation curve (ROC) analysis revealed that the area under curve (AUC) at year 5 was significantly increased from 0.762 to 0.819 after adding the risk score of these 3 SNPs to the clinical risk score. The remaining 32 SNPs were not significantly associated with NSCLC prognosis after adjustment for these 3 SNPs. These findings indicate that BID rs8190315, CASP9 rs4645981 and FAS rs1800682 polymorphisms in the apoptotic pathway may be involved in the prognosis of NSCLC in the Chinese population.     

小细胞和非小细胞肺癌晚期患者NK细胞表达的差异

目的:探索小细胞和非小细胞肺癌晚期患者NK细胞是否存在差异,并为治疗提供参考。方法:选取肺癌晚期患者共65例,其中包括小细胞肺癌14例,非小细胞肺癌51例以及20例健康对照。用流式细胞仪检测研究对象外周血淋巴细胞表面CD3-CD16+CD56+的表达情况。结果:小细胞肺癌晚期的患者较健康对照NK细胞显著升高;非小细胞肺癌晚期的患者较健康对照NK细胞无显著变化;肺癌晚期患者外周血NK细胞表达的百分比与CD4+T细胞表达的百分比呈负相关性。结论:小细胞肺癌晚期患者NK细胞升高,天然免疫可能成为已严重受损的细胞免疫的有力补充,但有待于进一步的研究。     

Glutathione-s-transferase M1 and T1 polymorphisms and associations with type 1 diabetes age-at-onset

Type 1 diabetes (T1D) is an autoimmune disease characterized by pancreatic beta cell destruction involving auto-reactive T-cells, pro-inflammatory cytokines, reactive oxygen species (ROS) and loss of insulin. Monozygotic twin studies show a 20–60% concordance with T1D indicating there may be an environmental component to the disease. Glutathione (GSH) is the major endogenous antioxidant produced by the cell. GSH participates directly in the neutralization of free radicals and plays a role in the immune response. Glutathione-s-transferases (GSTs) conjugate GSH to free-radicals or xenobiotics. GST activity depletes GSH levels and may either detoxify or enhance the toxicity of a compound. Glutathione-s-transferase mu 1 (GSTM1) and glutathione-s-transferase theta 1 (GSTT1) have polymorphic homozygous deletion (null) genotypes resulting in complete absence of enzyme activity. GSTM1 and GSTT1 null genotypes in Caucasian populations have frequencies of approximately 40–60% and 15–20%, respectively. GST null genotypes have been associated with susceptibility to cancer and protection against chronic pancreatitis. The aim of this study was to investigate associations with GSTM1 and GSTT1 polymorphisms in a group T1D patients and control subjects 0–35 years old who participated in the Combined Swedish Childhood Diabetes Registry and Diabetes Incidence Study (1986–1988). Results show that the presence of the GSTM1 and not the null genotype (OR, 2.13 95% CI, 1.23–3.70, p-value, 0.007, Bonferroni corrected p-value, 0.035) may be a susceptibility factor in T1D 14–20 years old. These results suggest that the GSTM1 null genotype is associated with T1D protection and T1D age-at-onset and that susceptibility to T1D may involve GST conjugation.     

ERCC1在非小细胞肺癌个体化治疗中的研究进展

非小细胞肺癌的发病率和病死率近年呈上升趋势,化学治疗(化疗)是治疗非小细胞肺癌的主要手段;但是由于耐药的存在,化疗疗效有效率有限,目前一线化疗联合方案的有效率仅为20%~40%。近年来随着肿瘤分子生物学的发展,已发现ERCC1等基因的表达水平和化疗药物疗效及预后密切相关,ERCC1的表达水平有可能成为预测疗效进行个体化治疗的重要指标。根据基因表达水平及药物敏感情况选择个体化的化疗方案是肿瘤学研究和临床肿瘤化疗的趋势。     

Role of GSTP1 Ile105Val and XRCC1 Arg194Trp,Arg280His and Arg399Gln gene polymorphisms in the clinical outcome of advanced non-small cell lung cancer

We conducted a study to investigate the association between the clinical outcome and GSTP1 Ile105Val and XRCC1 Arg194Trp, Arg280His and Arg399Gln gene polymorphisms in advanced NSCLC patients with cisplatin-based chemotherapy. Between January 2010 and December 2012, a total of 206 patients with advanced NSCLC were histopathologically confirmed were included into analysis. By logistic regression analysis, individuals carrying the AG and GG genotypes of GSTP1 Ile105Val were associated with better response to chemotherapy when compared with the AA genotype, and the adjusted Ors (95% CI) were 2.06 (1.10-3.86) and 4.89 (1.52-18.33), respectively. The TT genotype of XRCC1 Arg194Trp was correlated with better response to chemotherapy compared to the CC genotype, and the adjusted OR (95% CI) was 3.23 (1.20-9.30). By Cox Hazard Proportional Model, the GG genotype of GSTP1 Ile105Val and the TT genotype of XRCC1 Arg194Trp were found to be associated with lower risk of death from all causes when compared with the wide-type genotype, and the adjusted HRs (95% CI) were 0.05 (0.01-0.18) and 0.20 (0.07-0.62), respectively. Moreover, individuals carrying both the G/A+G/G genotype of GSTP1 Ile105Val and the G/A+A/A of XRCC1 Arg194Trp were associated with heavy greater CR+PR response to chemotherapy (OR=2.98, 95% CI=1.39-6.42), and also correlated with longer overall survival of advanced NSCLC (HR=0.19, 95% CI=0.05-0.61). In conclusion, we found that the GSTP1 Ile105Val and XRCC1 Arg194Trp were associated with better response to chemotherapy and longer survival of advanced NSCLC, compared to the wide-type genotype.     

埃克替尼治疗37例晚期非小细胞肺癌疗效分析

目的：探讨埃克替尼治疗晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的疗效及毒副作用。方法：回顾性分析未行表皮生长因子酪氨酸激酶抑制剂(EGFR-TKI)治疗的晚期NSCLC患者37例,给予盐酸埃克替尼125 mg,3次/d,口服治疗,直到病变进展或不能耐受。随访12个月,评估疗效并观察药物毒副反应。结果：本组37例患者均可评价疗效,客观缓解率(objective response rate,ORR)为56.7%(21/37),疾病控制率(disease control rate,DCR)为84.6%(35/37),中位无进展生存期(median progression free survival,mPFS)为6个月(95%CI：5.27~6.74)。不良反应主要为皮疹和腹泻,多为Ⅰ、Ⅱ度,均可耐受。结论：盐酸埃克替尼治疗晚期肺腺癌安全、有效,不良反应可耐受。     

恩度联合含铂类化疗方案治疗晚期非小细胞肺癌胸腔积液急性发作的临床疗效观察

目的：观察恩度联合含铂类化疗方案治疗晚期非小细胞肺癌胸腔积液急性发作的临床疗效。方法：选择2014年3月至2016年1月在我院接受治疗的晚期非小细胞肺癌胸腔积液急性发作患者100例,按照随机抽签的方式将其分为观察组和对照组,对照组患者给予单纯的含铂类化疗,观察组则给予恩度联合含铂类化疗,治疗结束后,观察两组的临床疗效。结果：治疗后,观察组的总缓解率为88%、生活质量总改善率为82%,明显的高于对照组的总缓解率56%、总改善率44%,两组比较差异具有统计学意义(P<0.05);治疗后,观察组胸水VEGF、HIF-1α水平分别为(334.7±81.4) pg/mL、(42.7±3.9) ng/L明显的低于对照组胸水VEGF水平(451.7±93.2) pg/mL、HIF-1α水平(48.9±3.2) ng/L,且观察组的肿瘤标记物水平明显的低于对照组,两组比较差异具有统计学意义(P<0.05);观察组在治疗期间总共发生69人次不良反应,对照组总共发生68人次不良反应,两组比较无显著差异(P>0.05)。结论：恩度联合含铂类化疗方案治疗晚期非小细胞肺癌胸腔积液急性发作具有显著的临床效果,有效地降低患者胸水VEGF、HIF-1α水平,且不会增加不良反应的发生。     

Glutathione S-transferases M1/T1 gene polymorphisms and endometriosis: a meta-analysis of genetic association studies

In view of the controversies surrounding the glutathione S-transferases (GST) M1/T1-endometriosis association, a meta-analysis of the GSTM1/GSTT1 genetic association studies of endometriosis was performed. In this meta-analysis involving 14 GSTM1 studies with 1539 cases and 1805 controls and nine GSTT1 studies with 746 cases and 834 controls, respectively, substantial heterogeneities among studies were found. In addition, asymmetry in funnel plot was evident, which is likely to stem from publication bias, given no apparent indication of true heterogeneity. The bias appears to be prominent for GSTM1 studies, but is less so for GSTT1 studies. After correction for this bias, there is no evidence that women with GSTM1 null genotype have increased risk of developing endometriosis as compared with women with other genotypes. For GSTT1, the risk associated with the null genotype is 29% higher than other genotypes. However, even this estimate should be viewed with a large grain of salt, because the estimate could easily lose its statistical significance if there is a realistic 69-80% publication probability.     

ROS1融合基因在非小细胞肺癌中的研究进展

非小细胞肺癌(non-small cell lung cancer,NSCLC)的分子靶向治疗是目前的研究热点,继EGFR、ALK基因等靶点之后不断有新的肿瘤标志物被发现。ROS1基因重排作为一种新发现的NSCLC亚型,其发生率约占NSCLC的1%~2%,优势人群通常为年轻、不吸烟的肺腺癌患者,这些临床特征与ALK重排的NSCLC患者类似。本文将NSCLC中发现的ROS1融合基因的研究进展及其在NSCLC中的临床、功能和结构特征进行阐述。     

韩国人CYP450 1A1、CYP450 2E1和GSTM1、GSTT1、GSTP1基因座遗传多态性分析

目的 调查代谢相关的CYP4501A1、CYP4502E1和GSTM1、GSIT1、GSTP1基因座在韩国人群中的遗传多态性分布状况。方法 采用多重聚合酶链式反应、聚合酶链式反应-限制性片段长度多态性技术，分析300名韩国健康大学生的CYP1A1基因3′端限制性内切酶Msp Ⅰ位点、CYP2E1基因5′端转录调节区Pst Ⅰ位点和GSTM1、GSTT1缺失与存在、GSTP1基因第5外显子BsmA Ⅰ位点的基因型，计算基因型和基因频率。结果 CYP1A1基因型频率为ml／ml型39．7％、ml／m2型49．7％、m2／m2型10．7％，基因频率为ml 0．645、m2 0．355。CYP2E1基因型频率为cl／cl型66．7％、cl／c2型30％、c2／c2型3．3％，基因频率为C1 0．818、C2 0．182。GSTM1基因缺失型频率为53．3％。GSTT1基因缺失型频率为54．7％。GSTP1基因型频率为Ile／Ile型62％、Ile／Val型34．3％、VaL／Val型3．7％，基因频率为Ile 0．792、Val 0．208。基因分布符合Hardy-Weirtberg平衡定律。结论 韩国人CYP1A1、CYP2E1、GSTM1、GSTT1基因分布与我国人群较为相近，半数以上人缺乏GSTM1和GSTT1基因，纯合缺失型频率超过印度人的3倍。     

ERCC1基因在非小细胞肺癌中的作用

化疗是非小细胞肺癌治疗的主要手段之一,而耐药是影响化疗疗效的重要因素。切除修复交叉互补基因1是核苷酸切除修复的关键基因,其基因表达及基因多态性与铂类耐药存在相关性,从而影响非小细胞肺癌对化疗敏感性及疗效。