BER修复基因多态性与肺癌易感性的研究进展

碱基切除修复(base excision repair,BER)通路是DNA损伤修复的关键通路,通路中的8-羟基鸟嘌呤DNA糖苷酶基因(human 8-oxoguanine glycosylase,hOGG1),人类X线交叉互补修复基因(X-ray repair cross-complementing group 1,XRCC1),MutY homolog(MUTYH)基因的单核苷酸多态性影响BER通路中重要的酶和蛋白质的功能,导致修复障碍,最终引起癌症发生.DNA损伤修复基因单核苷酸多态性和肺癌易感性的研究结果尚存在争议,本文对近年来BER通路基因hOGG1Ser326Cys,XRCC1 Arg194Trp,XRCC1 Arg280His,XRCC1 Arg399Gln,XRCC1-77T>C和MUTYHHis324Gln多态性与肺癌易感性的关系的研究进行汇总,并探讨了多项研究对BER基因多态性与不同肺癌亚型的关系以及与吸烟之间关系.基因多态性与肺癌易感性关系受多因素影响,其相关性尚待进一步探索.     

BER修复基因多态性与肺癌易感性的研究进展

碱基切除修复(base excision repair,BER)通路是DNA损伤修复的关键通路,通路中的8-羟基鸟嘌呤DNA糖苷酶基因(human 8-oxoguanine glycosylase,hOGG1),人类X线交叉互补修复基因(X-ray repair cross-complementing group 1,XRCC1),MutY homolog(MUTYH)基因的单核苷酸多态性影响BER通路中重要的酶和蛋白质的功能,导致修复障碍,最终引起癌症发生.DNA损伤修复基因单核苷酸多态性和肺癌易感性的研究结果尚存在争议,本文对近年来BER通路基因hOGG1Ser326Cys,XRCC1 Arg194Trp,XRCC1 Arg280His,XRCC1 Arg399Gln,XRCC1-77T>C和MUTYHHis324Gln多态性与肺癌易感性的关系的研究进行汇总,并探讨了多项研究对BER基因多态性与不同肺癌亚型的关系以及与吸烟之间关系.基因多态性与肺癌易感性关系受多因素影响,其相关性尚待进一步探索.     

DNA修复基因多态性与肺癌易感性的研究进展

肺癌是目前世界上死亡率最高的恶性肿瘤,其发病率在世界范围内呈逐年上升趋势。研究表明,DNA修复基因多态性可通过影响机体对DNA损伤的修复能力而使机体罹患癌症的风险发生变化。本文介绍了相关DNA修复基因多态性的研究进展,并就其多态与肺癌易感性的关系作一系统的人群基因组流行病学研究综述。     

DNA修复基因多态性与肺癌易感性的研究进展

肺癌是目前世界上死亡率最高的恶性肿瘤，其发病率在世界范围内呈逐年上升趋势。研究表明，DNA修复基因多态性可通过影响机体对DNA损伤的修复能力而使机体罹患癌症的风险发生变化。本文介绍了相关DNA修复基因多态性的研究进展，并就其多态与肺癌易感性的关系作一系统的人群基因组流行病学研究综述。     

肺癌遗传易感性研究进展

肺癌是人类最常见的恶性肿瘤之一,其发病原因与环境因素密不可分,但越来越多的研究表明遗传因素与肺癌易感性关系密切。本文对近几年致癌物代谢酶基因、DNA修复基因和抑癌基因与肺癌遗传易感性的关系的研究进展作一综述。     

肺癌遗传易感性研究进展

肺癌是全球发病率最高的恶性肿瘤之一。但其发病机制目前尚未阐明。近年来 ,肺癌的遗传易感性机制在肺癌发病中的意义引起人们的重视 ,抑瘤基因、代谢酶基因和修复酶基因的多态变异与肺癌遗传易感性的关系得到深入研究。本文综述了近年来肺癌遗传易感性研究的概况和进展     

基质金属蛋白酶1基因多态性与肺癌易感性的关联研究

目的研究我国西北汉族人群基质金属蛋白酶（matrix metalloproteinase 1，MMP1）基因-1607（1G→2G）多态与肺癌发生风险的关系。方法应用聚合酶链反应-限制性片段长度多态性分析的方法，检测了150例肺癌患者和200名正常对照者删1G→2G多态的基因型，比较不同基因型与肺癌发生风险的关系。结果肺癌组2G／2G基因型频率要高于对照组（X^2=5．896，P〈0．05），2G／2G基因型者患肺癌的风险是1G／2G和1G／1G基因型的1．77倍（OR=1．77；95％CI：1．12—2．91）。吸烟者中2G／2G基因型发生肺癌的风险是1G／2G和1G／1G基因型的3．20倍（OR=3．20；95％CI：1．50～6．82）。结论我国西北汉族人群MMP1基因-1607（1G→2G）多态性与肺癌易感性有关，2G／2G基因型可以增加肺癌发生风险。     

ATM基因rs227060位点单核苷酸多态性与肺癌易感性的相关性

目的:探讨共济失调毛细血管扩张症突变基因(ataxia telangiectasia mutated,ATM)rs227060位点单核苷酸多态性(single nucleotide polymorphisms,SNPs)与肺癌易感性之间的相关性.方法:采用聚合酶链反应-SNP敏感性分子开关方法,检测225例肺癌患者和128例健康体检者ATM基因rs227060多态位点等位基因以及基因型频率分布特点;并应用非条件Logistic回归法统计分析rs227060单核苷酸多态性与肺癌的相关性.结果:rs227060多态位点共检测出CC,CT,TT三种基因型和C,T两种等位基因,其在肺癌组与对照组的基因型分布频率为:CC基因型17.3％与29.7％、CT基因型61,4％与59.3％、TT基因型21.3％与11％,两组间基因型频率和等位基因频率分布差异均有统计学意义(P＜0.05).在对ATM rs227060基因型的多态性分析过程中发现:吸烟史在肺癌组与对照组相比差异无统计学意义(P＞0.05),而年龄、性别、肿瘤家族史在肺癌组与对照组相比差异均有统计学意义(P＜0.05);且以CC基因型作为对照,携带TT基因型的个体患肺癌的风险是携带CT基因型个体的3.49倍(OR=1.829;95％CI:1.045～3.199).结论:ATM基因rs227060位点单核苷酸多态性与肺癌易感性存在相关性,且携带TT基因型可增加肺癌的发病风险.     

细胞色素P450 2C19基因多态性与肺癌遗传易感性

目的 通过对肺癌组及对照组细胞色素P450 2C19(cytochrome P450 2C19,CYP2C19)等位基因进行基因分型,探讨CYP2C19基因中G681A和G636A多态性的分布与肺癌易感性的关系.方法 提取293例肺癌患者和300例健康对照组患者的外周血基因组DNA,用实时荧光PCR方法对CYP2C19进行基因分型.对肺癌组和健康对照组基因分布进行比较.结果 肺癌组CYP2C19* 2/*3基因型显著高于正常对照组,差异有统计学意义(18.77％ vs 5.67％;P=0.000),对照组CYP2C19* 1/*2基因型显著高于肺癌组,差异有统计学意义(30.67％ vs 13.99％;P=0.000).两组病例CYP2C19代谢型分布比较结果,肺癌组慢代谢型频率超过对照组一倍以上(33.45％ vs 15.33％).肺癌与各相关指标的多因素Logistic 相关分析结果显示,CYP2C19慢代谢型可能是肺癌发生的独立危险因素(P=0.000,OR:2.755,95％ CI:1.748 ～4.343).结论 CYP2C19慢代谢型可能与肺癌的发生有关.     

肺癌遗传易感性研究进展

肺癌是全球发病率最高的恶性肿瘤之一。但其发展机制目前尚未阐明。近年来,肺癌的遗传易感性机制在肺癌发病中的意义引起人们的重视,抑瘤基因、代谢酶基因和修复酶基因的多态变异与肺癌遗传易感性的关系到深入研究。本综述了近年来肺癌遗传易感性研究的概况和进展。     

Polymorphisms in DNA repair genes, chromosome aberrations, and lung cancer

We have previously investigated the role of polymorphic chemical metabolizing genes in the susceptibility to the development of lung cancer using 110 primary lung cancer patients and 119 matched smoker controls. Together with data from the present study on DNA repair genes, we did not observe significant associations between any single variant genotype for several DNA-repair and chemical-metabolizing genes (XPD [or ERCC2], XRCC1, XRCC3, GSTM1, GSTT1, MPO, and mEH [or EPHX1]) and lung cancer. In the present study, we have further evaluated a nested group of 79 patients and 69 matched controls, and observed that increased chromosome aberrations (CAs) were associated with variant DNA-repair genotypes among both the patient and the control groups, with a significant increase for individuals having the XPD Lys/Gln + Gln/Gln genotypes (P = 0.046). Patients often had significantly increased CAs compared with controls with the same DNA-repair genotype and with similar cigarette smoking habits (< or =40 pack-years or >40 pack-years). Analyses of interactions between the DNA-repair and chemical-metabolizing genes indicated that the most significant interactions were between the repair genotypes and the GSTM1/T1 null genotypes. Significant increases in CA from the interactions were often observed among patients with < or =40 pack-years, but not among those with >40 pack-years. Since some variant DNA-repair genotypes have functional deficits for DNA repair, the association between variant DNA-repair genotypes and increased CAs suggests a risk mechanism for the development of lung cancer, with the DNA-repair genotypes interacting with variant chemical metabolizing genotypes to further increase the risk. The observation that patients had significantly increased CA frequencies compared with controls, irrespective of genotype, suggests that patients have additional factors that contribute to the development of lung cancer.     

Association of single nucleotide polymorphisms of DNA repair gene and susceptibility to pancreatic cancer

We conducted a case-control study to assess the XRCC4 genes polymorphism and development of pancreatic cancer. A case-control study including 248 cases and 496 controls was conducted in a Chinese population. Genotypes of XRCC4 rs2075685, rs10040363, rs963248 and rs1805377 were determined using Polymerase Chain Reaction combined with a restriction fragment length polymorphism (PCR-RFLP) assay (Applied Biosystems, Foster City, CA, USA). Pancreatic cancer cases were more likely to have a history of diabetes, a higher BMI, family history of cancer and a habit of alcohol drinking when compared with control. Conditional logistic regression analysis showed that individuals carrying TT genotype of XRCC4 rs2075685 was associated with increased risk of pancreatic cancer when compared with GG genotype, and the OR (95% CI) was 1.62 (1.04-2.52). Individuals with GT+TT genotype of XRCC4 rs2075685 were significantly associated with increased risk of pancreatic cancer in those with ever tobacco smoking habit, and the OR (95% CI) was 1.77 (1.07-2.98). In conclusion, our results suggest that XRCC4 rs2075685 polymorphism plays an important role in the risk of pancreatic cancer in a Chinese population, especially in tobacco smokers.     

Polymorphisms in the DNA repair gene XRCC1 and age-related disease

The recent hypothesis that common variants (single nucleotide polymorphisms or SNPs) in the population may contribute significantly to genetic risk for common diseases permits a conceptually straightforward approach to identifying age-related disease-causing mutations. Functional variants of DNA replication and repair genes might be expected to be highly significant to cancer and aging since replication must proceed with high fidelity in a cellular environment where an estimated 10000 nucleotides are damaged daily. Single-strand breaks (SSB) are one of the results of DNA damage either by methylation, oxidation, reduction or fragmentation of bases by ionizing radiation, and arise in cells directly by disintegration of damaged sugars or indirectly as intermediates of base excision repair. Studies have demonstrated a role for XRCC1 both in vitro and in vivo during the repair of SSB. A number of SNPs have been identified for the XRCC1 gene, and several have been associated with age-related diseases, especially cancer. This report provides resequencing data confirming the existence of commonly occurring SNPs, including Arg194Trp and Arg399Gln, and briefly summarizes epidemiological and functional relevance to cancer and other age-related diseases. XRCC1 SNPs will be useful probes for investigating age-associated pathobiology in epidemiological and mechanistic studies.     

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.     

Influence of DNA repair gene polymorphisms on the yield of chromosomal aberrations

We evaluated the influence of several DNA repair gene polymorphisms on the frequency of chromosomal aberrations (CAs) analyzed in peripheral lymphocytes, using the fluorescence in situ hybridization technique. The CA data were obtained from an earlier study of 84 healthy nonsmokers (48 women and 36 men) carefully characterized for indoor radon exposure. The frequency of translocations showed a wide interindividual variability, which was only partly explained by age. To investigate the potential role of DNA repair polymorphisms in this variation, genotypes of DNA repair genes OGG1 (codon 326), XPD (codon 751), XRCC1 (X-ray repair cross-complementing group 1) (codons 194, 280, and 399), and XRCC3 (X-ray repair cross-complementing group 3) (codon 241) were determined from leukocyte DNA using polymerase chain reaction-based methods. Negative binomial regression models were applied to evaluate the effect of the polymorphisms and other factors (age, gender, radon exposure, and medical exposure) on the frequency of CAs. No interactions between genotypes and radon, medical exposure, or gender were found. Carriers of the XRCC1 codon 280His variant allele had a two-fold increase (frequency ratio [FR] = 2.01, 95% confidence interval [CI] = 1.01-3.98; P = 0.046) in unstable exchanges (dicentrics and ring chromosomes). In addition, the XRCC3 codon 241 homozygous variant genotype (Met/Met) was associated with an increase (FR = 1.70, 95% CI = 1.06-2.74; P = 0.028) in two-way translocations when age was taken into account in the analysis. Our data suggest that the XRCC1 280His and XRCC3 241Met alleles affect individual CA levels, most probably via influencing the DNA repair phenotype.     

Gene polymorphism in DNA repair genes XRCC1 and XRCC6 and association with colorectal cancer in Swedish patients

The DNA repair genes XRCC1 and XRCC6 have been proposed to participate in the pathological process of cancer by modulating the DNA repair capacity. This study evaluated the susceptibility of the single‐nucleotide polymorphisms (SNPs) XRCC1 (rs25487, G > A) and XRCC6 (rs2267437, C > G) to colorectal cancer (CRC) and their association with clinical parameters in Swedish patients with CRC. Using the TaqMan system, these SNPs were screened in 452 patients and 464 controls. No significant difference in genotype distribution was found between the patients and controls, or any significant association with cancer‐specific or disease‐free survival in patients. However, we showed that the carriers of allele A in XRCC1 (rs25487, G > A) were connected with a higher risk of disseminated CRC (Odds Ratio = 1.64; 95% Confidence Interval = 1.12–2.41, p = 0.012).     

Association between XRCC1 and XRCC3 gene polymorphisms and risk of thyroid cancer

We conducted a case-control study to examine the role of genetic polymorphisms in XRCC1 at codons 194 (Arg>Trp), 280 (Arg>His) and 399 (Arg>Gln) and XRCC3 at codon 241 (Thr>Met) in the risk of TC. This study included 276 consecutive primary TC patients and 552 control subjects. The genotypes of XRCC1 at codons 194 (Arg>Trp), 280 (Arg>His) and 399 (Arg>Gln) and XRCC3 at codon 241 (Thr>Met) were analyzed by PCR-RFLP. TT and CT+TT genotypes of XRCC1 194 (Arg>Trp) were significantly associated with increased risk of TC, and CC and TC+CC genotypes of XRCC3 241 (Thr>Met) revealed a significant associated with the TC risk. We only found that XRCC1 194 (Arg>Trp) and XRCC3 241 (Thr>Met) polymorphisms had interaction with smoking and drinking habits. In conclusion, the current study suggests that XRCC1 194 (Arg>Trp) and XRCC3 241 (Thr>Met) polymorphisms may be associated with TC risk in a Chinese population, especially in smokers and drinkers.