Association of DNA Base-excision Repair XRCC1, OGG1 and APE1 Gene Polymorphisms with Nasopharyngeal Carcinoma Susceptibility in a Chinese Population

Background: Numerous carcinogens and reactive oxygen species (ROS) may cause DNA damage includingoxidative base lesions that lead to risk of nasopharyngeal carcinoma. Genetic susceptibility has been reported toplay a key role in the development of this disease. The base excision repair (BER) pathway can effectively removeoxidative lesions, maintaining genomic stability and normal expression, with X-ray repair crosscomplementing1(XRCC1), 8-oxoguanine glycosylase-1 (OGG1) and apurinic/apyimidinic endonuclease 1 (APE1) playingimportant roles. Aims: To analyze polymorphisms of DNA BER genes (OOG1, XRCC1 and APE1) and exploretheir associations, and the combined effects of these variants, with risk of nasopharyngeal carcinoma. Materialsand Methods: We detected SNPs of XRCC1 (Arg399Gln), OGG1 (Ser326Cys), APE1 (Asp148Glu and -141T/G)using the polymerase chain reaction (PCR) with peripheral blood samples from 231 patients with NPC and 300healthy people, furtherly analyzing their relations with the risk of NPC in multivariate logistic regression models.Results: After adjustment for sex and age, individuals with the XRCC1 399Gln/Gln (OR=1.96; 95%CI:1.02-3.78; p=0.04) and Arg/Gln (OR=1.87; 95%CI:1.29-2.71; p=0.001) genotype variants demonstrated a significantlyincreased risk of nasopharyngeal carcinoma compared with those having the wild-type Arg/Arg genotype. APE1-141G/G was associated with a significantly reduced risk of NPC (OR=0.40;95%CI:0.18–0.89) in the smokinggroup. The OR calculated for the combination of XRCC1 399Gln and APE1 148Gln, two homozygous variants,was significantly additive for all cases (OR=2.09; 95% CI: 1.27-3.47; p=0.004). Conclusion: This is the first studyto focus on the association between DNA base-excision repair genes (XRCC1, OGG1 and APE1) polymorphismand NPC risk. The XRCC1 Arg399Gln variant genotype is associated with an increased risk of NPC. APE1-141G/G may decrease risk of NPC in current smokers. The combined effects of polymorphisms within BERgenes of XRCC1 399Gln and APE1 148Gln may contribute to a high risk of nasopharyngeal carcinoma.     

Breast Cancer Association Studies in a Han Chinese Population using 10 European-ancestry-associated Breast Cancer Susceptibility SNPs

Background: Genome-wide association studies (GWAS) have identified various genetic susceptibility loci forbreast cancer based mainly on European-ancestry populations. Differing linkage disequilibrium patterns existbetween European and Asian populations. Methods: Ten SNPs (rs2075555 in COL1A1, rs12652447 in FBXL17,rs10941679 in 5p12/MRPS30, rs11878583 in ZNF577, rs7166081 in SMAD3, rs16917302 in ZNF365, rs311499in 20q13.3, rs1045485 in CASP8, rs12964873 in CDH1 and rs8170 in 19p13.1) were here genotyped in 1009Chinese females (487 patients with breast cancer and 522 control subjects) using the Sequenom MassARRAYiPLEX platform. Association analysis based on unconditional logistic regression was carried out to determinethe odds ratio (OR) and 95% confidence interval (95% CI) for each SNP. Stratification analyses were carriedout based on the estrogen receptor (ER) and progesterone receptor (PR) status. Results: Among the 10 SNPs,rs10941679 showed significant association with breast cancer when differences between the case and controlgroups in this Han Chinese population were compared (30.09% GG, 45.4% GA and 23.7% AA; P = 0.012). FourSNPs (rs311499, rs1045485, rs12964873 and rs8170) showed no polymorphisms in our study. The remaining fiveSNPs showed no association with breast cancer in the present population. Immunohistochemical tests showedthat rs2075555 was associated with ER status; the AA genotype showed greater association with ER negativethan ER positive (OR = 0.54, 95% CI, 0.29–0.99; P = 0.046). AA of rs7166081 was also associated with ER status,but showed a greater association with ER positive than negative (OR = 1.59, 95% CI = 1.04–2.44; P = 0.031).However, no significant associations were found among the SNPs and PR status. Conclusion: In this study using aHan Chinese population, rs10941679 was the only SNP associated with breast cancer risk, indicating a differencebetween European and Chinese populations in susceptibility loci. Therefore, confirmation studies are necessarybefore utilization of these loci in Chinese.     

Association of CYP2E1, STK15 and XRCC1 Polymorphisms with Risk of Breast Cancer in Malaysian Women

Background: Breast cancer is the most common type of cancer affecting Malaysian women. Recent statistics revealed that the cumulative probability of breast cancer and related deaths in Malaysia is higher than in most of the countries of Southeast Asia. Single nucleotide polymorphisms (SNPs) in CYP2E1 (rs6413432 and rs3813867), STK15 (rs2273535 and rs1047972) and XRCC1 (rs1799782 and rs25487) have been associated with breast cancer risk in a meta-analysis but any link in Southeast Asia, including Malaysia, remained to be determined. Hence, we investigated the relationship between these SNPs and breast cancer risk among Malaysian women in the present case-control study. Materials and Methods: Genomic DNA was isolated from peripheral blood of 71 breast cancer patients and 260 healthy controls and subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Results: Our study showed that the c1/c2 genotype or subjects with at least one c2 allele in CYP2E1 rs3813867 SNP had significantly increased almost 1.8-fold higher breast cancer risk in Malaysian women overall. In addition, the variant Phe allele in STK15 rs2273535 SNP appeared to protect against breast cancer in Malaysian Chinese. No significance association was found between XRCC1 SNPs and breast cancer risk in the population. Conclusions: This study provides additional knowledge on CYP2E1, STK15 and XRCC1 SNP impact of risk of breast cancer, particularly in the Malaysian population. From our findings, we also recommend Malaysian women to perform breast cancer screening before 50 years of age.     

Association of DNA Repair Genes XRCC1 and APE-1 with the Risk of Cervical Cancer in North Indian population

Backgrounds: Cervical cancer (CC) is one of the leading cause of death in women worldwide, HPV infection is the major risk factor in the disease development, 0and however other risk factor such as chemical carcinogens, genetic susceptibility and altered immune system are also a cause of the disease progression. In the light of the above statement we studied the base excision repair pathway (BER). Methods: We identified and studied the association of Single Nucleotide polymorphisms in the DNA repair genes of XRCC1 (Arg194Trp, Arg399G,) and APE-1Asp/148Glu to the susceptibility of cervical cancer (CC) in North Indian population. In our study of cases (n=102). Controls (n=109) were recruited from among women without cervical abnormalities. Genotypes were determined by PCR-CTPP method, Taking DNA from peripheral blood in a case control study. Results: A positive association was observed between the polymorphisms of XRCC1 genes, that is, in codons 194 (P=0.03, odds ratio (OR) =2.39, 95% confidence interval (CI)=5.2–1.1), 280 (P=0.01, OR=4.1, 95% CI=11.5–1.3) and 399 (P=0.01, OR=3.4, 95% CI=8.6–1.3) while APE-1 genotype GG (p=0.03,odds ratio(OR)=0.2,95% confidence interval (CI)=0.97-0.004) we observed a statistically significant protective role in developing cervical cancer. Conclusion: Our results suggested that, XRCC1 gene is an important candidate gene for susceptibility to cervical cancer. Although the sample size was small, the present study indicate a statistical association between cervical cancer and XRCC1 SNPs. Future studies are needed that may provide a better understanding of the association between gene polymorphism and cervical carcinoma risk.     

Pathway-Affecting Single Nucleotide Polymorphisms (SNPs) in RPS6KA1 and MBIP Genes are Associated with Breast Cancer Risk

Background: Genetic mutations and polymorphisms play an important role in the transformation of primary cells to malignant cells as it may lead to disturbance of vital pathways regulating cell cycle, DNA damage repair, and apoptosis. In this study, we genotyped single nucleotide polymorphisms (SNPs) which were predicted to affect certain pathways and to increase the risk of breast cancer. Methods: The study included 81 Saudi breast cancer patients and 100 matching healthy controls from the Eastern Province in Saudi Arabia. The following SNPs (rs3168891, rs2899849, rs2230394, rs2229714) were then genotyped by TaqMan genotyping assay and the allele and genotype distribution was compared. Results: The minor allele frequency of the following SNPs (rs3168891, rs2899849, rs2230394, rs2229714) was T=0.17, A=0.28, A=0.22, and G=0.16 respectively. The G allele of the SNP rs3168891 was significantly associated with increased breast cancer risk (P = 0.00001) while the T allele of the same locus was associated with reduced risk of breast cancer in both heterozygous and homozygous states. The T allele of SNP rs2229714 which is located in the RPS6KA1 gene was also significantly associated with the increased risk of breast cancer. However, the rs2899849 SNP located in the Integrin beta-1 (ITGB1) gene was not associated with the increased risk of breast cancer in our study population. Haplotype analysis revealed the presence of three risk haplotypes that increases the risk of breast cancer (TGGT, TGTA, GATA). Conclusion: We showed that three, previously untested, SNPs are associated with increased risk of breast cancer in our population.  This may be added to the list of factors involved in breast cancer risk assessment studies. The benefit and the utility of the in-silico prediction of disease risk factors and their genetic association had been demonstrated in this study, yet the predicted risk alleles have to be tested in clinical studies.     

Polymorphisms of the XRCC1 and XPD Genes and Breast Cancer Risk: A Case-Control Study

The purpose of this case control study was to evaluate the role of X-ray repair cross-complementing group 1 (XRCC1) and xeroderma pigmentosum group D (XPD) genotypes as genetic indicators of susceptibility to breast cancer (BC). We analysed DNA samples from 114 breast cancer patients and 113 control subjects using polymerase chain reaction-restriction fragment length polymorphism. For the single nucleotide polymorphisms in XRCC1 exon 10 (Arg399Gln, G/A) and XPD exon 23 (Lys751Gln, A/C), no remarkable differences for genotype distribution and allele frequencies were observed between BC group and control group in the study. The genotype frequency for homozygote A/A in XPD exon 6 (Arg156Arg, C/A) were significantly different between BC and control groups (P < 0.0001, odds ratio = 2.14; 95% confidence interval 1.44-3.17). The data indicate a possible role for XPD (Arg156Arg, C/A) polymorphisms in BC susceptibility.     

Lack of Effects of Peroxisome Proliferator-Activated Receptor Gamma Genetic Polymorphisms on Breast Cancer Risk: a Case-Control Study and Pooled Analysis

A growing body of evidence suggests that the peroxisome proliferator-activated receptor-gamma (PPARγ)gene may harbor targets for the chemoprevention of breast cancer. However, it is unclear whether polymorphismsin the PPARγ gene are associated with the susceptibility of breast cancer. We performed a candidate geneassociation study between PPARγ polymorphisms and breast cancer and a meta-analysis on the association ofbreast cancer with selected PPARγ variants. Six single nucleotide polymorphisms (SNPs) in the PPARγ genewere analyzed among 456 breast cancer patients and 461 controls from the National Cancer Center in Korea.Association between the polymorphisms and breast cancer risk were assessed using the Cochrane-Armitage testfor trend and a multivariate logistic regression model. Two SNPs, rs3856806 and rs1801282, had been previouslyanalyzed, thus enabling us to perform pooled analyses on their associations with breast cancer susceptibility.Our findings from the candidate gene association study showed no association between the PPARγ genepolymorphisms and breast cancer risk. A meta-analysis combining existing studies and our current study alsorefuted an association of the PPARγ gene with breast cancer. Our findings suggest that the PPARγ gene may notharbor variants that alter breast cancer susceptibility, although a moderate sample size might have precludeda decisive conclusion.     

DNA修复基因XRCC1基因多态性与乳腺癌临床病理参数的相关性

目的 :研究XRCC1基因Arg194Trp和Arg399Gln多态性与中国女性乳腺癌临床病理参数的关系,探讨其在乳腺癌预后中的潜在意义。 方法 :采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法,对250例原发性乳腺癌患者进行XRCC1基因Arg194Trp、Arg399Gln多态性分析,用Pearsonχ²检验分析基因型与临床病理特征的关系。 结果 :XRCC1基因Arg194Trp和Arg399Gln多态性与乳腺癌患者的月经状态、肿瘤大小、腋窝淋巴结转移、TNM分期、雌激素受体均无显著相关性(P>0.05)。但该多态位点与乳腺癌患者的孕激素受体(PR)状态和C-erbB2蛋白表达显著相关。携带194纯合突变型的患者PR阴性率(81.0%)显著高于携带194野生型和杂合型患者(55.4%),(P=0.034);携带399纯合突变型的患者C-erbB2蛋白表达阳性率(61.1%)显著高于携带399野生型和杂合型的患者(29.3%),(P=0.006)。 结论 :PR阴性和(或)C-erbB2高表达的乳腺癌患者常提示预后不良。XRCC1基因多态性与PR阴性或C-erbB2高表达显著相关,提示携带XRCC1纯合突变(194或399)乳腺癌患者可能预后不良。     

No Association of XRCC1 and CLPTM1L Polymorphisms with Non-small Cell Lung Cancer in a Non-Smoking Han Chinese Population

Background: This study aimed to explore potential associations between single nucleotide polymorphisms(SNPs) of the x-ray repair cross-complementing group 1 (XRCC1) and cleft lip and palate transmembrane protein1-like (CLPTM1L) and non-small cell lung cancer (NSCLC) susceptibility in non-smoker Chinese patients.Methods: A total of 200 NSCLC patients and 200 healthy controls with matched age and gender were recruitedfor genotyping of XRCC1 SNPs (rs2256507 and rs1001581) and CLPTM1L SNPs (rs401681 and rs4975616).Association of these SNPs with NSCLC risk was evaluated by computing the odds ratio (OR) and 95% confidenceinterval (CI) from multivariate unconditional logistic regression analyses with adjustment for gender and age.Results: The frequencies of genotype and allele in these four loci (rs2256507, rs1001581, rs401681, and rs4975616)were not significantly different between the cases and controls, or between either of the histological subgroups(adenocarcinoma and squamous cell carcinoma) and controls. Conclusions: Although these SNPs are associatedwith NSCLC risk in patients with a tobacco-smoking habit, this study demonstrated that XRCC1 and CLPTM1Lgene SPNs are not linked with NSCLC risk in non-smoking patients, indicating that molecular mechanisms ofNSCLC betwee tobacco smokers and non-smokers may be different. Future studies are needed to uncover theunderlying molecular mechanisms for NSCLC in non-smokers.     

XRCC4 c.1394G>T Single Nucleotide Polymorphisms and Breast Cancer Risk among Filipinos

Background: The identification of cancer-associated single nucleotide polymorphisms (SNP) and mutationgenes is a promising approach in recognizing individuals who are at risk of developing cancer. Hence, this studywas conducted to determine the association between XRCC4 c.1394G>T SNP and breast cancer development amongFilipinos. Methods: Genotyping for XRCC4 c.1394G>T SNP was performed on breast cancer patients (n=103) andtheir age- and sex- matched clinically healthy controls (n=103) by polymerase chain reaction – restriction fragmentlength polymorphism. Results: Significant difference in genotype (p=0.007) and allele (p=0.003) frequencies in XRCC4c.1394G>T was observed between the breast cancer cases and controls. Carriers of the XRCC4 c.1394 G>T genotypewere observed to have significantly higher risk of developing breast cancer compared to individuals with T/T genotype(OR=2.67, 95% CI: 1.36 – 5.25). XRCC4 c.1394G>T combined with passive smoking may also significantly increaserisk of breast cancer (OR=14.73; 95% CI= 9.88-18.86). Conclusion: XRCC4 c. 1394G>T may be associated withbreast cancer development among Filipinos.     

Lack of Effects of Single Nucleotide Polymorphisms of the DNA Methyltransferase 1 Gene on Gastric Cancer in Iranian Patients: A Case Control Study

Background: Gastric cancer is one of the most common malignant tumors in Iran. Hypomethylation and/orhypermethylation of DNA has been described in gastric cancer and is presumed to be an early event incarcinogeneisis. Objective: We therefore hypothesized that single nucleotide polymorphisms of the DNMT1gene may be associated with the genetic susceptibility to gastric cancer. Methods: Totals of 200 patients and 200controls, both of Iranian origin, were studied. Three polymorphisms were genotyped by PCR-RFLP and allelefrequencies and genotypes were compared between the cases and controls. Odds ratios were calculated and theinteractions between the polymorphisms, age and sex were examined. Results : There were no significantassociations between the DNMT1 polymorphisms and gastric cancer. Conclusion: We could not show anyassociation between DNMT1 polymorphisms and gastric cancer. Larger sets of polymorphisms and samplesizes are required for future testing of possible associations.     

TNRC9 基因 rs12443621多态与中国人乳腺癌的相关性

 目的 探讨TNRC9 基因 rs12443621多态与中国妇女乳腺癌易感性及临床病理特征的关系。 方法 抽取321例乳腺癌患者和330例健康对照外周血,分离淋巴细胞,抽提基因组DNA,采用聚合酶链反应 连接酶检测反应(PCR-LDR)检测TNRC9 rs12443621基因多态,比较基因型分布和发病风险及临床病理特征的关系。危险度比值比(OR)及95％可信区间(CI)应用非条件Logistic回归分析计算。结果 Rs12443621 GG、AG和 AA基因型在病例组和对照组分别为 35.6%、46.3%、18.1%和 33.1%、48.1%、18.8%。 TNRC9 rs12443621基因型与发病年龄、淋巴结转移情况及雌、孕激素状态均无相关性。结论 TNRC9基因rs12443621多态与中国妇女乳腺癌易感性及临床病理特征无相关性。     

Association of XRCC1 Gene Polymorphisms with Breast Cancer Susceptibility in Saudi Patients

Background: X-ray repair cross-complementing group 1 (XRCC1) plays a key role in the base excision repairpathway, as a scaffold protein that brings together proteins of the DNA repair complex. XRCC1 is reported tobe a candidate influence on cancer risk. The aim of our present study was to assess the association of rs1799782(Arg194Trp) and rs25487 (Arg399Gln) XRCC1 gene polymorphisms with breast cancer in the Saudi population.Materials and Methods: The two SNP’s were analyzed in breast cancer patients and healthy control subjects.Genotypes were determined by TaqMan SNP genotype analysis technique and data were analyzed using Chisquareor t test and logistic regression analysis by SPSS16.0 software. Results and Conclusions: Results showedthat rs1799782 significantly increased susceptibility to breast cancer with Arg/Trp, Arg/Trp+Trp/Trp genotypesand at Trp allele overall study. It also increased risk of breast cancer in older age patients (above 48) and withthe ER positive category. XRCC1rs25487 (Arg399Gln) did not showed any significant association. In conclusionthe XRCC1rs1799782 polymorphism may be involved in the etiology of breast cancer in the Saudi population.Confirmation of our findings in larger populations of different ethnicities is warranted.     

Lack of any Association of the CTLA-4 +49 G/A Polymorphism with Breast Cancer Risk in a North Indian Population

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an important protein involved in the regulation of theimmune system. The +49 G/A polymorphism is the only genetic variation in the CTLA-4 gene that causes anamino acid change in the resulting protein. It is therefore the most extensively studied polymorphism among allCTLA-4 genetic variants and contributions to increasing the likelihood of developing cancer are well known invarious populations, especially Asians. However, there have hiterto been no data with respect to the effect of thispolymorphism on breast cancer susceptibility in our North Indian population. We therefore assayed genomicDNA of 250 breast cancer subjects and an equal number of age-, sex- and ethnicity-matched healthy controlsfor the CTLA-4 +49 G/A polymorphism but no significant differences in either the gene or allele frequency werefound. Thus the CTLA-4 +49 G/A polymorphism may be associated with breast cancer in other Asians, but itappears to have no such effect in North Indians. The study also highlights the importance of conducting geneticassociation studies in different ethnic populations.     

Polymorphisms in base excision repair genes: Breast cancer risk and individual radiosensitivity

Breast cancer (BC) is the most common cancer among women worldwide. The aetiology and carcinogenesis of BC are not clearly defined, although genetic, hormonal, lifestyle and environmental risk factors have been established. The most common treatment for BC includes breast-conserving surgery followed by a standard radiotherapy (RT) regimen. However, radiation hypersensitivity and the occurrence of RT-induced toxicity in normal tissue may affect patients’ treatment. The role of DNA repair in cancer has been extensively investigated, and an impaired DNA damage response may increase the risk of BC and individual radiosensitivity. Single nucleotide polymorphisms (SNPs) in DNA repair genes may alter protein function and modulate DNA repair efficiency, influencing the development of various cancers, including BC. SNPs in DNA repair genes have also been studied as potential predictive factors for the risk of RT-induced side effects. Here, we review the literature on the association between SNPs in base excision repair (BER) genes and BC risk. We focused on X-ray repair cross complementing group 1 (XRCC1), which plays a key role in BER, and on 8-oxoguanine DNA glycosylase 1, apurinic/apyrimidinic endonuclease 1 and poly (ADP-ribose) polymerase-1, which encode three important BER enzymes that interact with XRCC1. Although no association between SNPs and radiation toxicity has been validated thus far, we also report published studies on XRCC1 SNPs and variants in other BER genes and RT-induced side effects in BC patients, emphasising that large well-designed studies are needed to determine the genetic components of individual radiosensitivity.     

DNA Repair Gene Polymorphisms at XRCC1, XRCC3, XPD,and OGG1 Loci in the Hyderabad Population of India

Background: DNA repair is one of the crucial defense mechanism against mutagenic exposure. Inherited SNPs of DNA repair genes may contribute to variation in DNA repair capacity and susceptibility to cancer. Due to thepresence of these variants, inter-individual and ethnic differences in DNA repair capacity have been established in various populations. India harbors enormous genetic and cultural diversity. Materials and Methods: In the present study we aimed to determine the genotypes and allele frequencies of XRCC1 Arg399Gln (rs25487), XRCC3 Thr241Met (rs861539), XPD Lys751Gln (rs13181), and OGG1 Ser326Cys (rs1052133) gene polymorphisms in 186 healthy individuals residing in the Hyderabad region of India and to compare them with HapMap and otherpopulations. Results and Conclusions: The genotype and allele frequency distribution at the four DNA repairgene loci among Hyderabad population of India revealed a characteristic pattern. Comparison of these genepolymorphisms with other populations revealed a distinctiveness of Hyderabad population from the Deccanregion of India. To the best of our knowledge, this is the first report of such DNA repair gene polymorphisms inthe Deccan Indian population.     

Genetic Risk of DNA Repair Gene Polymorphisms (XRCC1 and XRCC3) for High Risk Human Papillomavirus Negative Cervical Cancer in Northeast Thailand

To identify risk factors other than high risk human papillomavirus infection for the development of cervicalcancer, functional polymorphisms of DNA repair genes, XRCC1 Arg399Gln and Arg194Trp and XRCC3Thr241Met, were studied among Northeastern Thai women. Cases (n=111) were defined as squamous cellcervical cancer and controls (n=118) were recruited from healthy women without cervical abnormalities. TheXRCC1 194Trp/Trp genotype significantly increased the risk for cervical cancer (OR=5.52; 95%CI=1.14-26.64;p=0.03). Among the HPV infection negative group, significantly higher risks for cervical cancer were visualizedfor XRCC1 399Arg/Gln (adjusted OR=3.69; 95%CI=1.04-13.06; p=0.04) and XRCC1 194Arg/Trp (adjustedOR=4.13; 95%CI=1.13-15.12; p=0.03). This study indicates that variant types of DNA repair genes play partialroles in modifying individual susceptibility to cervical cancer. Since cervical cancer is a multi-factorial disease,the contribution of DNA repair enzymes to the development of cervical cancer, if it exists may be concealed byHPV infection.