Gene Summary

Gene:XRCC3; X-ray repair cross complementing 3
Aliases: CMM6
Summary:This gene encodes a member of the RecA/Rad51-related protein family that participates in homologous recombination to maintain chromosome stability and repair DNA damage. This gene functionally complements Chinese hamster irs1SF, a repair-deficient mutant that exhibits hypersensitivity to a number of different DNA-damaging agents and is chromosomally unstable. A rare microsatellite polymorphism in this gene is associated with cancer in patients of varying radiosensitivity. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:DNA repair protein XRCC3
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: XRCC3 (cancer-related)

Liu HX, Li J, Ye BG
Correlation between gene polymorphisms of CYP1A1, GSTP1, ERCC2, XRCC1, and XRCC3 and susceptibility to lung cancer.
Genet Mol Res. 2016; 15(4) [PubMed] Related Publications
Lung cancer is a common malignant tumor that is characterized by high morbidity and poor prognosis. Studies suggest that an individual's genetic background affects the risk of developing lung cancer. Therefore, we investigated the relationship between gene polymorphisms and susceptibility to lung cancer. We recruited 308 primary lung cancer patients as subjects and 253 healthy adults as controls. After extraction of DNA from blood samples, gene polymorphisms in CYP1A1, GSTP1, ERCC2, XRCC1, and XRCC3 were investigated by polymerase chain reaction and restriction fragment length polymorphism. The frequencies of the genotypes in both groups were investigated to obtain odds ratios and 95% confidence intervals, and correlation analysis was carried out. The analysis results showed that the following polymorphisms were correlated with susceptibility to lung cancer: rs4646903 in CYP1A1 (P < 0.001), rs1048943 in CYP1A1 (P < 0.001), rs1695 in GSTP1 (P < 0.05), rs13181 in ERCC2 (P < 0.001), and rs25487 in XRCC1 (P < 0.05); no such correlation existed in rs861539 in XRCC3 (P > 0.05). The study revealed that the more high-risk gene polymorphisms a patient carries, the greater the risk of developing lung cancer. Carriers of rs4646903 in CYP1A1, rs1048943 in CYP1A1, rs1695 in GSTP1, rs13181 in ERCC2, and rs25487 in XRCC1 are more likely to develop lung cancer.

Ravegnini G, Nannini M, Simeon V, et al.
Polymorphisms in DNA repair genes in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome.
Tumour Biol. 2016; 37(10):13413-13423 [PubMed] Related Publications
DNA repair pathways play an essential role in cancer susceptibility by maintaining genomic integrity. This led us to investigate the influence of polymorphisms in the genes coding repair pathway enzymes on gastrointestinal stromal tumours (GIST) susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 20 polymorphisms in 11 genes in 81 cases and 147 controls. The XPD rs13181 wild-type allele and hOGG1 rs1052133 and XPF rs1800067 minor alleles were significantly associated with disease susceptibility. XPA rs1800975 and rs2808668 were associated with tumour size (P = 0.018), metastatic status at onset (P = 0.035) and mitotic index (P = 0.002). With regards to outcome treatment, the XPD rs50872 minor allele had a significant favourable impact on time to progression (TTP). Similarly, the XPC rs2228000 minor allele was correlated with a longer TTP (P = 0.03). On the contrary, the XPC rs2228001 and hOGG1 rs1052133 minor alleles were associated with a diminished TTP (P = 0.005 and P = 0.01, respectively). Regarding OS, we found the presence of at least one hOGG1 (rs1052133) minor allele that had a 60 % lower risk to die compared to the wild-type carriers (P = 0.04). Furthermore, the XRCC3 rs861539 variant allele is associated with a hazard of early death compared with the wild-type genotype (P = 0.04). To the best of our knowledge, this is the first study on polymorphisms in DNA repair genes, belonging to the different pathways, extensively evaluated in GIST patients. Through this multiple candidate gene approach, we report for the first time the significant associations between polymorphisms in DNA repair genes, susceptibility, clinical pathological features and clinical outcome in GIST.

Yan L, Li Q, Li X, et al.
Association Studies Between XRCC1, XRCC2, XRCC3 Polymorphisms and Differentiated Thyroid Carcinoma.
Cell Physiol Biochem. 2016; 38(3):1075-84 [PubMed] Related Publications
BACKGROUND/AIMS: DNA HRR pathway and BER pathway play vital roles in differentiated thyroid cancer (DTC) development, thus we supposed that polymorphisms of XRCC1, XRCC2, XRCC3 DNA repair genes are associated with thyroid cancer risk and progression.
METHODS: We searched the NCBI database for relevant literatures to determine eight SNPs to be included in our study (XRCC1: rs25487, rs25489, rs1799782; XRCC2: rs3218536; XRCC3: rs1799794, rs56377012, rs1799796, rs861539).
RESULTS: SNP of rs25487 was linked with a 53% decrease in DTC risk (OR: 0.47; 95%CI: 0.268-0.82; P = 0.01). For SNP of rs1799782, the homozygous TT genotype indicated a statistically significant 2-fold increased risk of DTC (OR: 2.09; 95%CI: 1.27-3.43; P < 0.001) after multivariate adjustment. For SNP of rs861539, the homozygous TT genotype suggested statistically significant 3-fold increased risk of DTC (OR: 3.02; 95%CI: 1.68-5.42; P < 0.001). No significant association between the other five SNPs and DTC risk. Besides that, female was linked with 47% increase in DTC risk (OR: 1.47; 95%CI: 1.062-2.04; P = 0.02) after multivariate adjustment. Similar results for most of the SNPs were obtained from subgroup analysis by different histological types of DTC. Haplotype analysis revealed that AGC and GGT haplotypes of XRCC1 polymorphisms were associated with DTC. Moreover, results from gene-gene interaction showed that XRCC1-rs25487, XRCC1- rs1799782 and XRCC3- rs861539 variants jointly contributed to a specifically increased risk of DTC, with the combination variant of rs1799782-CT heterozygote and rs861539-TT homozygote exhibiting a higher 3.66-fold risk of DTC (OR: 3.66; 95% CI: 1.476-9.091, P = 0.005).
CONCLUSION: Polymorphisms of XRCC1 (rs25487, rs1799782) and XRCC3 (rs861539), may play a critical role in DTC development and progression. Furthermore, XRCC1 variant can interact with XRCC3 variant to significantly increase DTC susceptibility. Identifying these genetic risk markers could provide evidence for exploring the insight pathogenesis and develop novel therapeutic strategies for DTC.

Li F, Wang J, Chen M
Single nucleotide polymorphisms in DNA repair genes and the risk of laryngeal cancer: A meta-analysis.
Biomed Pharmacother. 2016; 78:92-100 [PubMed] Related Publications
Laryngeal cancer is the most common type of head and neck cancer with poor prognosis and high relapse rate. Several genes involved in DNA repair pathways have been identified for their potential role in laryngeal cancer risk. However, the results remain inconclusive. The aim of this study was to investigate the association between polymorphisms of XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln and laryngeal cancer risk. Relevant case-control studies published between 2000 and 2015 were retrieved. The odds ratio (OR) with its 95% confidence interval (CI) were employed to calculate the strength of correction. Finally, total 16 articles (8 for XRCC1 Arg399Gln variant, 8 for XRCC3 Thr241Met variant and 7 for XPD Lys751Gln variant) were screened out, including 2242 laryngeal cancer cases and 3811 matched controls. Overall, our results found that only AA genotype of the XRCC1 gene Arg399Gln polymorphism under the homozygous model was associated with increased the risk of patients with laryngeal cancer (AA vs. GG: OR=1.29, 95% CI=1.00-1.65, P=0.05). This significant relationship was not detected between XRCC3 Thr241Met, XPD Lys751Gln polymorphisms and laryngeal cancer risk (P>0.05). In conclusions, our results suggested that XRCC1 gene Arg399Gln polymorphism might be a risk factor for laryngeal cancer. Future studies with large-scales, more ethnicities are still needed to further evaluate the role of these three genes mutations in laryngeal cancer susceptibility.

Ali AM, AbdulKareem H, Al Anazi M, et al.
Polymorphisms in DNA Repair Gene XRCC3 and Susceptibility to Breast Cancer in Saudi Females.
Biomed Res Int. 2016; 2016:8721052 [PubMed] Free Access to Full Article Related Publications
We investigated three common polymorphisms (SNPs) in the XRCC3 gene (rs861539, rs1799794, and rs1799796) in 143 Saudi females suffering from breast cancer (median age = 51.4 years) and 145 age matched normal healthy controls. DNA was extracted from whole blood and genotyping was conducted using PCR-RFLP. rs1799794 showed significant association, where AA and AA+AG occurred at a significantly higher frequency in the cancer patients compared to the control group (OR: 28.1; 95% CI: 3.76-21.12; χ (2): 22.82; p < 0.0001). The G allele was protective and presented with a dominant model. The genotype and allele frequencies of rs861539 C>T and rs1799796 A>G did not show a significant difference when the results in the patients and controls were compared. However, the frequency of rs1799796 differed significantly in patients with different age of diagnosis, tumor grade, and ER and HER2 status. The wild type A allele occurred at a higher frequency in the ER- and HER2- group. Our results among Saudis suggest that some variations in XRCC3 may contribute to breast cancer susceptibility. In conclusion, the results obtained during this study suggest that rs1799794 in XRCC3 shows strong association with breast cancer development in Saudi females.

Michalska MM, Samulak D, Romanowicz H, et al.
Association between single nucleotide polymorphisms (SNPs) of XRCC2 and XRCC3 homologous recombination repair genes and ovarian cancer in Polish women.
Exp Mol Pathol. 2016; 100(2):243-7 [PubMed] Related Publications
The variability, perceived in DNA repair genes, may be of clinical importance for evaluation of the risk of occurrence of a given type of cancer, its prophylactics and therapy. The aim of the present work was to evaluate associations between the risk of ovarian cancer and polymorphisms in the genes, encoding for two key proteins of homologous recombination: XRCC2 Arg188His (c. 563 G>A; rs3218536) and XRCC3 Thr241Met (c. 722 C>T; rs861539). The study consisted of 700 patients with ovarian cancer and 700 healthy subjects. Analysis of the gene polymorphisms was performed using PCR-RFLP (restriction length fragment polymorphism). We found a statistically significant increase of the 188His allele frequency (OR=4.01; 95% CI=3.40-4.72; p<.0001) of XRCC2 in ovarian cancer compared to healthy controls. There were no differences in the genotype and allele distributions and odds ratios of the XRCC3 Thr241Met polymorphism between patient and control groups. Association of these genetic polymorphisms with histological grading showed increased XRCC2 188Arg/His (OR=33.0; 95% CI=14.51-75.05; p<.0001) and 188His/His genotypes (OR=9.37; 95% CI=4.79-18.32; p<.0001) and XRCC3 241Thr/Met (OR=24.28; 95% CI=12.38-47.61; p<.0001) and 241Met/Met genotype frequencies (OR=17.00; 95% CI=8.42-34.28; p<.0001) in grading 1 (G1) as well as 188His (OR=2.78; 95% CI=2.11-3.69; p<.0001) and 241Met allele overrepresentation (OR=2.59; 95% CI=2.08-3.22; p<.0001) in G1 ovarian patients. Finally, with clinical FIGO staging under evaluation, an increase in XRCC2 188His/His homozygote and 188Arg/His heterozygote frequencies in staging I (SI) and XRCC3 Thr/Met heterozygote frequencies in SI was observed. The obtained results indicate that XRCC2 Arg188His and XRCC3 Thr241Met polymorphisms may be positively associated with the incidence of ovarian carcinoma in the population of Polish women.

Xie YQ, Chen JM, Liu Y
Interaction of the CYP1A1 gene polymorphism and smoking in non-small cell lung cancer susceptibility.
Genet Mol Res. 2016; 14(4):19411-7 [PubMed] Related Publications
Many studies have shown that genetic factors, environmental factors, and bad living habits, especially smoking, are risk factors for lung cancer. However, not all smokers develop lung cancer, which may be related to different genetic backgrounds. Currently, most research has investigated the GSTM1, XRCC1, XRCC3, CYP2D6, and C188T genes. Little research has been done on the cytochrome P450 (CYP) 1A1 gene, and results have varied. In addition, no results have been reported on the interactive effects of smoking and the CYP1A1 gene on lung cancer development. We used polymerase chain reaction restriction fragment length polymorphism to detect the CYP1A1 genotype, and investigate the effects of the CYP1A1 gene deletion and smoking alone, and in combination, on non-small cell lung cancer susceptibility. We enrolled 150 non-small cell lung cancer patients and 150 healthy control subjects. Subjects' smoking habits and CYP1A1 gene polymorphism were analyzed to investigate their role in the occurrence of lung cancer. The CYP1A1 gene deletion was found in 73.3% of non-small cell lung cancer patients and 20.0% of healthy subjects. The OR value was 2.28 (P < 0.05). Among smoking subjects, 77.8% exhibited non-small cell lung cancer, significantly higher than the 27.3% in non-smokers (P < 0.05). The OR value for the interaction of smoking and CYP1A1 gene deletion was 5.60, larger than the product of their individual OR values. The CYP1A1 gene deletion is a lung cancer risk factor, and interacts with smoking in non-small cell lung cancer development.

dos Santos Pereira J, Fontes FL, de Medeiros SR, et al.
Association of the XPD and XRCC3 gene polymorphisms with oral squamous cell carcinoma in a Northeastern Brazilian population: A pilot study.
Arch Oral Biol. 2016; 64:19-23 [PubMed] Related Publications
OBJECTIVE: to evaluate the association between XPD and XRCC3 polymorphisms and oral squamous cell carcinoma (OSCC).
DESIGN: the sample consisted of 54 cases of OSCC and 40 cases of inflammatory fibrous hyperplasia (IFH). Genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.
RESULTS: XPD-Lys/Gln was more common in IFH (n=28; 70%) than in OSCC (n=24; 44.4%) (OR: 0.3; p<0.05). XPD-Gln was more frequent in high-grade lesions (0.48) than in low-grade lesions (0.21) (OR: 3.4; p<0.05). The Gln/Gln genotype was associated with III and IV clinical stages (OR: 0.07; p<0.05). XRCC3-Met was more frequent in OSCC (0.49) than in IFH (0.35) (OR: 2.6; p<0.05). The Met/Met genotype was associated with the presence of metastases (OR: 8.1; p<0.05) and with III and IV clinical stages (OR: 0.07; p<0.05).
CONCLUSIONS: in this sample, the frequency of XPD-Gln in IFH suggests that this variant may protect against OSCC. The presence of the XRCC3-Met allele seems to contribute to the development of OSCC, metastases and more advanced stages in these lesions.

Lu W, Wu G, Zhang B
Association Between X-Ray Cross-complementing Group 3 (XRCC3) Thr241Met Polymorphism and Risk of Thyroid Cancer: A Meta-Analysis.
Med Sci Monit. 2015; 21:3978-85 [PubMed] Free Access to Full Article Related Publications
BACKGROUND The X-ray cross-complementing group 3 (XRCC3) gene encodes a protein that plays an important role in homologous recombination repair (HRR) of DNA double-strand break (DSB). Increasing attention has been drawn to the association of XRCC3 T241M polymorphism with various types of human cancers. In this study, a meta-analysis was performed to investigate whether there is an association between XRCC3 T241M polymorphism and thyroid cancer risk. MATERIAL AND METHODS A comprehensive search was conducted and a total of 8 studies that covered 963 thyroid cancer cases and 1942 controls were included in this analysis. The meta-analysis was performed on both overall database and 2 ethnic subgroups (Caucasian and Asian). The fixed-effects model was used to calculate odds ratio (OR) with 95% confidence intervals (CIs). The publication bias was evaluated using Begg's funnel plots and Egger's test. RESULTS A positive association between XRCC3 T241M polymorphism and thyroid cancer risk was found by the analyses of the overall database using both recessive model (OR=1.40, 95% CI=1.08-1.81, P=0.012) and homozygote comparison (OR=1.41, 95% CI=1.07-1.86, P=0.015), but not by that using the dominant model (OR=1.12, 95% CI=0.95-1.33, P=0.18). However, no significant association of XRCC3 Thr241Met polymorphism with the risk of thyroid cancer was found in individual ethnic subgroups. CONCLUSIONS We conclude that the XRCC3 Thr241Met polymorphism is associated with an increased risk of thyroid cancer in the overall population, while no significant association was observed in individual ethnic subgroups due to limited population size.

Loghin A, Bănescu C, Nechifor-Boila A, et al.
XRCC3 Thr241Met and XPD Lys751Gln gene polymorphisms and risk of clear cell renal cell carcinoma.
Cancer Biomark. 2016; 16(2):211-7 [PubMed] Related Publications
INTRODUCTION: In the last decade, an increasing number of polymorphisms in DNA repair genes have been identified and their involvement in carcinogenesis was studied. Despite the fact that XRCC3 and XPD DNA repair genes association with several types of cancer was widely studied, their role in the development of clear cell renal cell carcinoma (CCRCC) has not been established in the European population.
OBJECTIVE: The objective of this study was to investigate the association of XRCC3 Thr241Met and XPD Lys751Gln gene polymorphisms with the risk of CCRCC and the association between these genotypes and CCRCC histopathological prognostic factors (pathologic stage, Fuhrman grade, tumor diameter).
METHODS: This study included 73 patients with CCRCC and 100 healthy individuals without cancer. We used the PCR-RFLP method to determine XRCC3 and XPD genotypes.
RESULTS: The XPD 751 variant genotype (Lys/Gln) was more frequent in CCRCC patients than in healthy individuals (OR = 2.92, 95%CI: 1.47-5.79, p= 0.001). Regarding the XRCC3 Thr241Met/XPD Lys751Gln combined genotypes a significant difference was found between patients and controls for Thr/Thr+Lys/Gln (OR = 5.44, 95%CI: 2.09-14.15, p= 0.0003) and for Thr/Met+Gln/Gln (OR = 11.2, 95%CI: 1.95-100.4, p= 0.01).No association was found between any of the studied genotypes and histopathological prognostic factors of CCRCC.
CONCLUSIONS: Our findings indicate that XPD Lys751Gln polymorphism may be a risk factor for CCRCC. Regarding the XRCC3 Thr241Met polymorphism, an association with CCRCC was found only in XRCC3 Thr241Met/XPD Lys751Gln combined genotypes.

Guo J, Lv HC, Shi RH, Liu WL
Association between XRCC3 Thr241Met polymorphism and risk of osteosarcoma in a Chinese population.
Genet Mol Res. 2015; 14(4):16484-90 [PubMed] Related Publications
Osteosarcoma is one of the most common bone malignancies in adolescents, and hereditary factors may influence its susceptibility. We assessed the association between XRCC3 Thr241Met polymorphism and susceptibility to osteosarcoma in a Chinese population. Between May 2012 and May 2014, a total of 136 osteosarcoma patients and 136 healthy control subjects were included in our study. The XRCC3 Thr241Met polymorphism was analyzed using a polymerase chain reaction restriction fragment length polymorphism assay. By multiple logistic regression analysis, individuals carrying the Met/Met genotype of XRCC3 Thr241Met were at significantly increased risk of osteosarcoma when compared with the Thr/Thr (OR = 2.50, 95%CI = 1.13-5.66). The Thr/Met+Met/Met genotype of XRCC3 Thr241Met was furthermore found to be correlated with an elevated increased risk of osteosarcoma when compared with the Thr/Thr genotype (OR = 1.71, 95%CI = 1.03-2.87), and Met/Met genotype of XRCC3 Thr241Met was associated with an increased risk of osteosarcoma compared to the Thr/Thr (OR = 3.50, 95%CI = 1.51-8.79). In conclusion, our study firstly reports that XRCC3 Thr241Met gene polymorphism is associated with an elavated risk of osteosarcoma.

Ji RB, Qian YS, Hu AR, Hu YR
DNA repair gene XRCC3 T241M polymorphism and susceptibility to hepatocellular carcinoma in a Chinese population: a meta-analysis.
Genet Mol Res. 2015; 14(4):15988-96 [PubMed] Related Publications
Numerous studies have evaluated the association between the X-ray repair complementing defective repair in Chinese hamster cells 3 (XRCC3) T241M polymorphism and hepatocellular carcinoma (HCC) risk. However, the results of such investigations have proved inconsistent. Therefore, we performed a meta-analysis of the association between this polymorphism and HCC risk in the Chinese population. Published literature from PubMed and China National Knowledge Infrastructure databases was retrieved, and a total of 5 case-control studies consisting of 2967 patients and 3874 controls were included in this meta-analysis, which revealed a significant association between the XRCC3 T241M polymorphism and HCC risk (TT vs MM: OR = 6.54, 95%CI = 2.14-19.99; TT vs MT: OR = 4.72, 95%CI = 2.26-9.86; dominant model: OR = 0.38, 95%CI = 0.26-0.57; recessive model: OR = 1.27, 95%CI = 0.99-1.62). In a subgroup analysis by sample size (number of subjects > 1000), similar results were obtained. Thus, XRCC3 T241M polymorphism may constitute a risk factor for HCC in the Chinese population.

Yang L, An Y, Wang G, et al.
Association between XRCC3 Thr241Met polymorphism and risk of osteosarcoma in a Chinese population.
Int J Clin Exp Pathol. 2015; 8(9):11670-4 [PubMed] Free Access to Full Article Related Publications
The aim of this study was to investigate whether XRCC3 Thr241Met polymorphism could affect the development of osteosarcoma in a Chinese population. A total of 152 osteosarcoma patients and 304 health control subjects were included in our study. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay was applied to assess the XRCC3 Thr241Met gene polymorphism. By conditional logistic regression analysis, we found that TT genotype of XRCC3 Thr241Met was associated with increased risk of osteosarcoma in codominant model (OR = 2.53, 95% CI = 1.28-5.39). Moreover, XRCC3 Thr241Met gene polymorphism was correlated with an elevated increased risk of osteosarcoma in dominant (OR = 1.55, 95% CI = 1.03-2.34) and recessive models (OR = 2.30, 95% CI = 1.16-4.56). In conclusion, we found that XRCC3 Thr241Met gene polymorphism was associated with increased risk of osteosarcoma in codominant, dominant and recessive models.

Zhang LZ, Li YS, Liu HZ
Meta-analysis of the relationship between XRCC3 T241M polymorphism and colorectal cancer susceptibility.
Genet Mol Res. 2015; 14(4):14831-9 [PubMed] Related Publications
Numerous studies have evaluated the relationship between the T241M polymorphism of the X-ray repair cross-complementing group 3 (XRCC3) gene and colorectal cancer (CRC) risk. However, the specific relationship remains controversial. We conducted meta-analysis to investigate the relationship between the XRCC3 T241M polymorphism and CRC risk. The PubMed and Embase databases were searched for relevant studies investigating the relationship between the XRCC3 T241M polymorphism and CRC risk. The odds ratio (OR) and 95% confidence interval (CI) were used to assess the possible relationship. Thirteen individual case-control studies, including 4720 cases and 6104 controls, were identified and included in this meta-analysis. Meta-analyses revealed no relationship between the XRCC3 T241M polymorphism and CRC risk (TT vs MM: OR = 0.85, 95%CI = 0.63-1.14; TT vs MT: OR = 0.87, 95%CI = 0.68-1.10; dominant model: OR = 1.18, 95%CI = 0.92-1.50; recessive model: OR = 0.87, 95%CI = 0.69-1.11). In the further subgroup analysis by ethnicity, we found no direct relationship between the polymorphism and CRC risk in either Asians or Europeans. Our findings demonstrated that the T241M polymorphism in the XRCC3 gene may not be a risk factor for CRC development.

Su CH, Chang WS, Hu PS, et al.
Contribution of DNA Double-strand Break Repair Gene XRCC3 Genotypes to Triple-negative Breast Cancer Risk.
Cancer Genomics Proteomics. 2015 Nov-Dec; 12(6):359-67 [PubMed] Related Publications
AIM: The DNA-repair gene X-ray repair cross-complementing group 3 (XRCC3) is important in DNA double-strand break repair and plays a critical part in initiation of carcinogenesis. Triple-negative breast cancer (TNBC) is the most difficult breast cancer subtype with no existing gene-targeting drugs and little knowledge on its genetic etiology. This study aimed to investigate the contribution of the XRCC3 genotype to individual TNBC susceptibility.
MATERIALS AND METHODS: A total of 2,464 Taiwan citizens consisting of 1,232 breast cancer cases and 1,232 controls were enrolled in this case-control study, and genotyping of XRCC3 rs1799794, rs45603942, rs861530, rs3212057, rs1799796, rs861539 and rs28903081 were performed with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We also conducted risk-stratified sub-group analyses to determine the association between the genotype and age- and hormone-related characteristics of breast cancer sub-groups.
RESULTS: There was no significant difference between breast cancer and control groups in the distributions of the genotypic or allelic frequencies as for the XRCC3 rs1799794 (p=0.5195 and 0.9545), rs45603942 (p=0.3478 and 0.1449), rs861530 (p=0.4567 and 0.5081), rs3212057 (p=1.0000 and 1.0000), rs1799796 (p=0.8487 and 0.7315) and rs28903081 (p=1.0000 and 1.0000), respectively. However, the XRCC3 rs861539 TT genotype was more prevalent in patients with breast cancer [odds ratio (OR)=2.99, 95% confidence interval (CI)=1.62-5.55; p=0.0002], and especially among those who were younger than 55 years (OR=2.61, 95% CI=1.82-3.73; p=0.0001), with first menarche earlier than 12.2 years (OR=2.47, 95% CI=1.74-3.52; p=0.0001), with menopause at 49.0 years old or later (OR=2.53, 95% CI=1.76-3.62; p=0.0001), or with TNBC (OR=2.05, 95% CI=1.46-4.28; p=4.63*10(-4)).
CONCLUSION: XRCC3 rs861539 TT is a potential predictive marker for TNBC in Taiwanese women and investigations in other populations are warranted for further universal application in cancer detection and prediction.

Franceschi S, Tomei S, Mazzanti CM, et al.
Association between RAD 51 rs1801320 and susceptibility to glioblastoma.
J Neurooncol. 2016; 126(2):265-70 [PubMed] Related Publications
Glioblastoma is the most common and aggressive malignant primary brain tumor. Despite decades of research and the advent of new therapies, patients with glioblastoma continue to have a very poor prognosis. Radiation therapy has a major role as adjuvant treatment for glioblastoma following surgical resection. Many studies have shown that polymorphisms of genes involved in pathways of DNA repair may affect the sensitivity of the cells to treatment. Although the role of these polymorphisms has been investigated in relation to response to radiotherapy, their role as predisposing factors to glioblastoma has not been clarified yet. In the present study, we evaluated the association between polymorphisms in DNA repair genes, namely: XRCC1 rs25487, XRCC3 rs861539 and RAD51 rs1801320, with the susceptibility to develop glioblastoma. Eighty-five glioblastoma patients and 70 matched controls were recruited for this study. Data from the 1000 Genomes Project (98 Tuscans) were also downloaded and used for the association analysis. Subjects carrying RAD51 rs1801320 GC genotype showed an increased risk of glioblastoma (GC vs GG, χ(2) = 10.75; OR 3.0087; p = 0.0010). The C allele was also significantly associated to glioblastoma (χ(2) = 8.66; OR 2.5674; p = 0.0032). Moreover, RAD51 rs1801320 C allele increased the risk to develop glioblastoma also when combined to XRCC1 rs25487 G allele and XRCC3 rs861539 C allele (χ(2) = 6.558; p = 0.0053).

Stur E, Agostini LP, Garcia FM, et al.
Prognostic significance of head and neck squamous cell carcinoma repair gene polymorphism.
Genet Mol Res. 2015; 14(4):12446-54 [PubMed] Related Publications
The aims of this study were to analyze the polymorphisms XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, XPC Lys939Gln, ERCC1 Asn118Asn, and RAD51 -98G>C and to verify their influence on radiotherapy response and prognosis of patients with head and neck squamous cell carcinoma (HNSCC). Peripheral blood DNA was extracted from 311 patients and analyzed by PCR-RFLP. Our results showed that in irradiated oral and oropharyngeal patients, the 939Gln allele increased 6-fold local disease relapse risk (OR = 6.04; CI = 1.47-24.88) and over 2-fold the earliness of relapse (HR = 2.63; CI = 1.04-6.70). As for the XRCC3 polymorphism, multivariate analysis showed that the 241Met allele increases over 33-fold local relapse risk (OR = 33.64; CI = 3.23-350.85), over 12-fold earliness of relapse (HR = 12.55; CI = 2.47-63.73) and over 3-fold earliness of death (HR = 3.04; CI = 1.08-8.61). For polymorphism RAD51 -98, multivariate analysis showed that allele C increases over 3-fold the risk of relapse (OR = 3.13; CI = 1.12-8.78) and over 2-fold the earliness of relapse (HR = 2.84; CI = 1.25-6.47). For polymorphism XRCC1 Arg399Gln, multivariate analysis showed that the 399Gln allele increased the risk of local disease relapse for irradiated oral and oropharyngeal patients (OR = 3.35; CI = 1.10-10.13) by over 3-fold. Based on these results, we suggest that these polymorphisms may be useful markers of prognosis in HNSCC.

Chai F, Liang Y, Chen L, et al.
Association between XRCC3 Thr241Met Polymorphism and Risk of Breast Cancer: Meta-Analysis of 23 Case-Control Studies.
Med Sci Monit. 2015; 21:3231-40 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Studies have shown that gene and environmental factors, such as BRCA1/2 mutations, ionized radiation, and chemical carcinogens, are related with breast cancer. X-ray repair cross-complementing group 3 (XRCC3) is involved in homologous repair of double DNA breaks. It was reported that Thr241Met single-nucleotide polymorphism (SNP) in XRCC3 is associated with increased risk of breast cancer. However, the finding remains controversial. The current meta-analysis aims to determine whether XRCC3 Thr241Met polymorphism is associated with increased risk of breast cancer.
MATERIAL AND METHODS: We performed a meta-analysis of association between XRCC3 T241M polymorphism and the risk of breast cancer. Crude odds ratios (ORs) together with 95% confidence intervals (CIs) were used to assess the strength of association in dominant, recessive, and homozygote models.
RESULTS: We included 23 studies consisting of 13513 cases and 14100 controls in our study. For meta-analysis on the entire database, association of the SNP and breast cancer risk was observed in recessive (OR=1.10, 95% CI: 1.03-1.18, p=0.005) and homozygote (OR=1.09, 95% CI: 1.01-1.18, p=0.023) models. For the analysis on the Asian population subgroup, association of the SNP and breast cancer risk was also observed in recessive (OR=1.615, 95% CI: 1.17-2.228, p=0.004) and homozygote (OR=1.609, 95% CI: 1.154-2.241, p=0.005) models. For the evaluation of the patients without family history of breast cancer, association of the SNP and breast cancer risk was observed in dominant (OR=1.364, 95% CI: 1.096-1.698, p=0.005), recessive (OR=1.336, 95% CI: 0.999-1.788, p=0.051) and homozygote (OR=1.492, 95% CI: 1.085-2.051, p=0.014) models.
CONCLUSIONS: We can conclude that XRCC3 Thr241Met polymorphism might be associated with breast cancer risk, especially in Asian populations and in patients without family history of breast cancer.

Middleton FK, Patterson MJ, Elstob CJ, et al.
Common cancer-associated imbalances in the DNA damage response confer sensitivity to single agent ATR inhibition.
Oncotarget. 2015; 6(32):32396-409 [PubMed] Free Access to Full Article Related Publications
ATR is an attractive target in cancer therapy because it signals replication stress and DNA lesions for repair and to S/G2 checkpoints. Cancer-specific defects in the DNA damage response (DDR) may render cancer cells vulnerable to ATR inhibition alone. We determined the cytotoxicity of the ATR inhibitor VE-821 in isogenically matched cells with DDR imbalance. Cell cycle arrest, DNA damage accumulation and repair were determined following VE-821 exposure.Defects in homologous recombination repair (HRR: ATM, BRCA2 and XRCC3) and base excision repair (BER: XRCC1) conferred sensitivity to VE-821. Surprisingly, the loss of different components of the trimeric non-homologous end-joining (NHEJ) protein DNA-PK had opposing effects. Loss of the DNA-binding component, Ku80, caused hypersensitivity to VE-821, but loss of its partner catalytic subunit, DNA-PKcs, did not. Unexpectedly, VE-821 was particularly cytotoxic to human and hamster cells expressing high levels of DNA-PKcs. High DNA-PKcs was associated with replicative stress and activation of the DDR. VE-821 suppressed HRR, determined by RAD51 focus formation, to a greater extent in cells with high DNA-PKcs.Defects in HRR and BER and high DNA-PKcs expression, that are common in cancer, confer sensitivity to ATR inhibitor monotherapy and may be developed as predictive biomarkers for personalised medicine.

Huang JY, Yang JF, Qu Q, et al.
DNA repair gene XRCC3 variants are associated with susceptibility to glioma in a Chinese population.
Genet Mol Res. 2015; 14(3):10569-75 [PubMed] Related Publications
The susceptibility to glioma is not well understood. It has been suggested that the X-ray cross complementing group 3 (XRCC3) gene influences the capacity to repair DNA damage, leading to increased glioma susceptibility. In this study, we evaluated the relationship between XRCC3 mutations and glioma risk. Genotypes were assessed in 389 Chinese glioma patients and 358 healthy controls. XRCC3 Thr241Met (rs861539) and 2 additional polymorphisms, rs3212112 (c.774+19T>G) and rs1799796 (c.562-14A>G), were directly sequenced. The frequency of the rs861539 T allele was significantly lower in the glioma group than in healthy controls [11.1 vs 17.7%, odds ratio = 0.62 (0.48-0.80), P < 0.001]; the frequencies of the CT or CT+TT genotypes differed between groups (18.5 vs 31%, 20.3 vs 33.2%, respectively). The frequency of the rs3212112 G allele was significantly higher in the glioma group than in healthy controls [15.8 vs 5.3%, odds ratio = 2.94 (2.07-4.17), P < 0.001]. The frequencies of the GT or TG+GG genotypes differed between groups (25.4 vs 7.8%, 28.5 vs 9.2%, respectively). This study demonstrates that the rs861539 and rs3212112 polymorphisms in the XRCC3 gene may influence the risk of glioma development in Chinese populations.

Nowacka-Zawisza M, Wiśnik E, Wasilewski A, et al.
Polymorphisms of homologous recombination RAD51, RAD51B, XRCC2, and XRCC3 genes and the risk of prostate cancer.
Anal Cell Pathol (Amst). 2015; 2015:828646 [PubMed] Free Access to Full Article Related Publications
Genetic polymorphisms in DNA repair genes may induce individual variations in DNA repair capacity, which may in turn contribute to the risk of cancer developing. Homologous recombination repair (HRR) plays a critical role in maintaining chromosomal integrity and protecting against carcinogenic factors. The aim of the present study was to evaluate the relationship between prostate cancer risk and the presence of single nucleotide polymorphisms (SNPs) in the genes involved in HRR, that is, RAD51 (rs1801320 and rs1801321), RAD51B (rs10483813 and rs3784099), XRCC2 (rs3218536), and XRCC3 (rs861539). Polymorphisms were analyzed by PCR-RFLP and Real-Time PCR in 101 patients with prostate adenocarcinoma and 216 age- and sex-matched controls. A significant relationship was detected between the RAD51 gene rs1801320 polymorphism and increased prostate cancer risk. Our results indicate that the RAD51 gene rs1801320 polymorphism may contribute to prostate cancer susceptibility in Poland.

Yuan K, Huo M, Sun Y, et al.
Association between x-ray repair cross-complementing group 3 (XRCC3) genetic polymorphisms and papillary thyroid cancer susceptibility in a Chinese Han population.
Tumour Biol. 2016; 37(1):979-87 [PubMed] Related Publications
Papillary thyroid cancer (PTC) is a predominant type of thyroid cancer. Ionizing radiation is the only well-established risk factor and may result in double-strand breaks. The x-ray repair cross-complementing group 3 (XRCC3) gene plays a vital role in DNA repair through homologous recombination. We aimed at investigating the association between XRCC3 genetic polymorphisms and PTC susceptibility. Eighty-three PTC patients and 367 controls in a Chinese population were enrolled in the study. Tag single-nucleotide polymorphisms (SNPs) were identified by HaploView 4.2 software. Genomic DNAs were isolated from peripheral blood samples by using TaqMan Blood DNA kits. The genotyping of XRCC3 SNPs was performed by TaqMan SNPs genotyping assay. Odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) were calculated to evaluate the association between XRCC3 SNPs and PTC susceptibility. The statistical analyses were conducted by using SPSS 13.0 software. Four tag-SNPs were initially identified by HaploView 4.2 software. Only one SNP (rs861539) was shown to be significantly associated with increased risk of PTC. There was a significant difference in smoking and drinking status between PTC cases and controls. And the stratified analysis suggested that the polymorphisms of rs861539 in XRCC3 were correlated with PTC risk in the four subgroups of smokers (ex-smokers included), non-smokers, drinkers (ex-drinkers included), and non-drinkers. The meta-analysis showed that only two studies reported a significant association between XRCC3 polymorphisms and PTC risk. In this study, we find a significant association between rs861539 polymorphisms and PTC susceptibility. However, there were inconsistent results in previous published studies. Therefore, further studies in a large population are required to gain insights into the PTC risk conferred by XRCC3 SNPs.

Kjersem JB, Thomsen M, Guren T, et al.
AGXT and ERCC2 polymorphisms are associated with clinical outcome in metastatic colorectal cancer patients treated with 5-FU/oxaliplatin.
Pharmacogenomics J. 2016; 16(3):272-9 [PubMed] Related Publications
The objective of the study was to investigate whether specific single nucleotide polymorphisms (SNPs) with influence on drug transport, biotransformation and repair mechanisms are associated with treatment outcome and toxicity in metastatic colorectal cancer (mCRC). We genotyped blood samples from 519 mCRC patients treated with first-line 5-fluorouracil and oxaliplatin +/- cetuximab for 17 SNPs in 10 genes involved in membrane transport (ABCC1 and ABCC2), drug biotransformation (GSTP1 and AGXT) and DNA repair (ERCC1, ERCC2, XRCC1, XRCC3, XPG and MSH6). The AGXT-rs34116584 and the ERCC2-rs238406 polymorphisms were significantly associated with progression-free survival (P=0.002 and P=0.001, respectively). Associations between 18 toxicity variables and SNPs were identified, although none were significant after Bonferroni correction for multiple comparisons. The study identified SNPs of potential use as markers of clinical outcome in oxaliplatin-treated mCRC patients. If validated in other studies, they could improve the selection of therapy in mCRC.

Chang WS, Tsai CW, Wang JY, et al.
Contribution of X-Ray Repair Complementing Defective Repair in Chinese Hamster Cells 3 (XRCC3) Genotype to Leiomyoma Risk.
Anticancer Res. 2015; 35(9):4691-6 [PubMed] Related Publications
AIM: The present study aimed at investigating whether X-ray repair cross complementing protein 3 (XRCC3) genotype may serve as a useful marker for detecting leiomyoma and predicting risk.
MATERIALS AND METHODS: A total of 640 women (166 patients with leiomyoma and 474 healthy controls) were examined for their XRCC3 rs1799794, rs45603942, rs861530, rs3212057, rs1799796, rs861539, rs28903081 genotype. The distributions of genotypic and allelic frequencies between the two groups were compared.
RESULTS: The results showed that the CT and TT genotypes of XRCC3 rs861539 were associated with increased leiomyoma risk (odds ratio=2.19, 95% confidence interval=1.23-3.90; odds ratio=3.72, 95% confidence interval=1.23-11.26, respectively). On allelic frequency analysis, we found a significant difference in the distribution of the T allelic frequency of the XRCC3 rs861539 (p=5.88 × 10(-5)). None of the other six single nucleotide polymorphisms were associated with altered leiomyoma susceptibility.
CONCLUSION: The T allele (CT and TT genotypes) of XRCC3 rs861539 contributes to increased risk of leiomyoma among Taiwanese women and may serve as a early detection and predictive marker.

Su Y, Zhang H, Xu F, et al.
DNA Repair Gene Polymorphisms in Relation to Non-Small Cell Lung Cancer Survival.
Cell Physiol Biochem. 2015; 36(4):1419-29 [PubMed] Related Publications
BACKGROUND: Single nucleotide polymorphisms (SNPs) in the DNA repair genes are suspected to be related to the survival of lung cancer patients due to their possible influence on DNA repair capacity (DRC). However, the study results are inconsistent.
METHODS: A follow-up study of 610 non-small cell lung cancer (NSCLC) patients was conducted to investigate genetic polymorphisms associated with the DNA repair genes in relation to NSCLC survival; 6 SNPs were genotyped, including XRCC1 (rs25487 G>A), hOGG1 (rs1052133 C>G), MUTYH (rs3219489 G>C), XPA (rs1800975 G>A), ERCC2 (rs1799793 G>A) and XRCC3 (rs861539 C>T). Kaplan- Meier survival curve and Cox proportional hazards regression analyses were performed. SNP-SNP interaction was also examined using the survival tree analysis.
RESULTS: Advanced disease stage and older age at diagnosis were associated with poor prognosis of NSCLC. Patients with the variant 'G' allele of hOGG1 rs1052133 had poor overall survival compared with those with the homozygous wild 'CC' genotype, especially in female patients, adenocarcinoma histology, early stage, light smokers and without family history of cancer. For never smoking female lung cancer patients, individuals carrying homozygous variant 'AA' genotype of XPA had shorter survival time compared to those with wild 'G' alleles. Furthermore, females carrying homozygous variant XPA and hOGG1 genotypes simultaneously had 2.78-fold increased risk for death. Among all 6 polymorphisms, the homozygous variant 'AA' of XPA carriers had poor prognosis compared to the carriers of wild 'G' alleles of XPA together with other base excision repair (BER) polymorphisms.
CONCLUSIONS: Besides disease stage and age, the study found DNA repair gene polymorphisms were associated with lung cancer survival.

Chen HJ, Chang WS, Hsia TC, et al.
Contribution of Genotype of DNA Double-strand Break Repair Gene XRCC3, Gender, and Smoking Behavior to Lung Cancer Risk in Taiwan.
Anticancer Res. 2015; 35(7):3893-9 [PubMed] Related Publications
AIM: The present study evaluated the contribution of genotype of X-ray repair cross-complementing group 3 (XRCC3), age, gender, and smoking to lung cancer risk in Taiwan.
MATERIALS AND METHODS: A total of 358 patients with lung cancer and 716 controls were investigated for their XRCC3 rs1799794, rs45603942, rs861530, rs3212057, rs1799796, rs861539, rs28903081 genotype, epidemiological and clinical data for association and gene-Iifestyle interactions.
RESULTS: The results showed that CT and TT genotypes of XRCC3 rs861539 were associated with increased lung cancer risk (odds ratio=1.81, 95% confidence interval=1.18-2.78; odds ratio=3.43, 95% confidence interval=1.12-10.60, respectively). This polymorphism also influenced lung cancer susceptibility in males and smokers (p=0.0017 and 0.0045, respectively).
CONCLUSION: The T allele of XRCC3 rs861539 contributes to increased risk of lung cancer in Taiwanese, particularly those who are male and smokers.

Boldrin E, Rumiato E, Fassan M, et al.
Genetic risk of subsequent esophageal cancer in lymphoma and breast cancer long-term survival patients: a pilot study.
Pharmacogenomics J. 2016; 16(3):266-71 [PubMed] Related Publications
The occurrence of a second primary esophageal carcinoma (EC) in long-term cancer survivors may represent a late effect of previous radio-chemotherapeutic treatment. To identify the genetic factors that could increase this risk, we analyzed nine variants within ERCC1, XPD, XRCC1 and XRCC3 DNA repair pathway genes, and GSTP1, TP53 and MDM2 genes in 61 patients who received radio-chemotherapy for a prior lymphoma or breast cancer; 29 of them had a second primary EC. This cohort consists of 22 esophageal squamous cell carcinoma (ESCC) and 7 esophageal adenocarcinoma (EADC) patients. A validation cohort of 154 patients with sporadic EC was also included. The XPD Asp312Asn (rs1799793) was found to be associated with the risk of developing second primary ESCC (P=0.015). The resultant variant was also involved in the onset of sporadic ESCC (P=0.0018). To know in advance who among long-term cancer survivors have an increased risk of EC could lead to a more appropriate follow-up strategy.

Wang X, Zhang K, Liu X, et al.
Association between XRCC1 and XRCC3 gene polymorphisms and risk of thyroid cancer.
Int J Clin Exp Pathol. 2015; 8(3):3160-7 [PubMed] Free Access to Full Article Related Publications
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.

Agostini M, Zangrando A, Pastrello C, et al.
A functional biological network centered on XRCC3: a new possible marker of chemoradiotherapy resistance in rectal cancer patients.
Cancer Biol Ther. 2015; 16(8):1160-71 [PubMed] Free Access to Full Article Related Publications
Preoperative chemoradiotherapy is widely used to improve local control of disease, sphincter preservation and to improve survival in patients with locally advanced rectal cancer. Patients enrolled in the present study underwent preoperative chemoradiotherapy, followed by surgical excision. Response to chemoradiotherapy was evaluated according to Mandard's Tumor Regression Grade (TRG). TRG 3, 4 and 5 were considered as partial or no response while TRG 1 and 2 as complete response. From pretherapeutic biopsies of 84 locally advanced rectal carcinomas available for the analysis, only 42 of them showed 70% cancer cellularity at least. By determining gene expression profiles, responders and non-responders showed significantly different expression levels for 19 genes (P < 0.001). We fitted a logistic model selected with a stepwise procedure optimizing the Akaike Information Criterion (AIC) and then validated by means of leave one out cross validation (LOOCV, accuracy = 95%). Four genes were retained in the achieved model: ZNF160, XRCC3, HFM1 and ASXL2. Real time PCR confirmed that XRCC3 is overexpressed in responders group and HFM1 and ASXL2 showed a positive trend. In vitro test on colon cancer resistant/susceptible to chemoradioterapy cells, finally prove that XRCC3 deregulation is extensively involved in the chemoresistance mechanisms. Protein-protein interactions (PPI) analysis involving the predictive classifier revealed a network of 45 interacting nodes (proteins) with TRAF6 gene playing a keystone role in the network. The present study confirmed the possibility that gene expression profiling combined with integrative computational biology is useful to predict complete responses to preoperative chemoradiotherapy in patients with advanced rectal cancer.

Verde Z, Reinoso L, Chicharro LM, et al.
Are SNP-Smoking Association Studies Needed in Controls? DNA Repair Gene Polymorphisms and Smoking Intensity.
PLoS One. 2015; 10(5):e0129374 [PubMed] Free Access to Full Article Related Publications
Variations in tobacco-related cancers, incidence and prevalence reflect differences in tobacco consumption in addition to genetic factors. Besides, genes related to lung cancer risk could be related to smoking behavior. Polymorphisms altering DNA repair capacity may lead to synergistic effects with tobacco carcinogen-induced lung cancer risk. Common problems in genetic association studies, such as presence of gene-by-environment (G x E) correlation in the population, may reduce the validity of these designs. The main purpose of this study was to evaluate the independence assumption for selected SNPs and smoking behaviour in a cohort of 320 healthy Spanish smokers. We found an association between the wild type alleles of XRCC3 Thr241Met or KLC3 Lys751Gln and greater smoking intensity (OR = 12.98, 95% CI = 2.86-58.82 and OR=16.90, 95% CI=2.09-142.8; respectively). Although preliminary, the results of our study provide evidence that genetic variations in DNA-repair genes may influence both smoking habits and the development of lung cancer. Population-specific G x E studies should be carried out when genetic and environmental factors interact to cause the disease.

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