XRCC4

Gene Summary

Gene:XRCC4; X-ray repair cross complementing 4
Aliases: SSMED
Location:5q14.2
Summary:The protein encoded by this gene functions together with DNA ligase IV and the DNA-dependent protein kinase in the repair of DNA double-strand breaks. This protein plays a role in both non-homologous end joining and the completion of V(D)J recombination. Mutations in this gene can cause short stature, microcephaly, and endocrine dysfunction (SSMED). Alternative splicing generates several transcript variants. [provided by RefSeq, Dec 2015]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:DNA repair protein XRCC4
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
Show (29)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Vertebrates
  • Smoking
  • Breast Cancer
  • Protein-Serine-Threonine Kinases
  • Double-Stranded DNA Breaks
  • Odds Ratio
  • DNA-Activated Protein Kinase
  • Registries
  • Polymorphism
  • Ubiquitin-Protein Ligases
  • DNA Repair Enzymes
  • Case-Control Studies
  • Cervical Cancer
  • p53 Protein
  • Ku Autoantigen
  • Antigens, Nuclear
  • DNA Sequence Analysis
  • Lung Cancer
  • DNA Helicases
  • Risk Factors
  • Radiation Tolerance
  • Cancer Gene Expression Regulation
  • Radiation, Ionizing
  • DNA-Binding Proteins
  • Poland
  • DNA Ligase ATP
  • XRCC4
  • Genetic Recombination
  • Chromosome 5
  • bcl-2-Associated X Protein
  • Genotype
  • DNA End-Joining Repair
  • DNA Ligases
  • DNA Damage
  • DNA Repair
  • Single Nucleotide Polymorphism
  • Polymerase Chain Reaction
  • Alleles
  • Haplotypes
  • Bladder Cancer
  • Genetic Predisposition
  • Nuclear Proteins
Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: XRCC4 (cancer-related)

Sanie-Jahromi F, Saadat I, Saadat M
Effects of extremely low frequency electromagnetic field and cisplatin on mRNA levels of some DNA repair genes.
Life Sci. 2016; 166:41-45 [PubMed] Related Publications
AIMS: It has been shown that exposure to extremely-low frequency (˂300Hz) oscillating electromagnetic field (EMF) can affect gene expression. The effects of different exposure patterns of 50-Hz EMF and co-treatment of EMF plus cisplatin (CDDP) on mRNA levels of seven genes involved in DNA repair pathways (GADD45A, XRCC1, XRCC4, Ku70, Ku80, DNA-PKcs and LIG4) were evaluated.
MAIN METHODS: Two 50-Hz EMF intensities (0.25 and 0.50mT), three exposure patterns (5min field-on/5min field-off, 15min field-on/15min field-off, 30min field-on continuously) and two cell lines (MCF-7 and SH-SY5Y) were used. The mRNA levels were measured using quantitative real-time PCR.
KEY FINDINGS: The examined genes had tendency to be down-regulated in MCF-7 cells treated with EMF. In the pattern of 15min field-on/15min field-off of the 0.50mT EMF, no increase in mRNA levels were observed, but the mRNA levels of GADD45A, XRCC1, XRCC4, Ku80, Ku70, and LIG4 were down-regulated. A significant elevation in IC50 of CDDP was observed when MCF-7 and SH-SY5Y cells were co-treated with CDDP+EMF in comparison with the cells treated with CDDP alone. GADD45A mRNA levels in MCF-7 and SH-SY5Y cells co-treated with CDDP+EMF were increased and at the same time the mRNA levels of XRCC4, Ku80, Ku70 and DNA-PKcs were down-regulated.
SIGNIFICANCE: Present study provides evidence that co-treatment of CDDP+EMF can enhance down-regulation of the genes involved in non-homologous end-joining pathway. It might be suggested that co-treatment of CDDP+EMF could be more promising for sensitizing cancer cells to DNA double strand breaks.

Liu K, Jiang Y
Polymorphisms in DNA Repair Gene and Susceptibility to Glioma: A Systematic Review and Meta-Analysis Based on 33 Studies with 15 SNPs in 9 Genes.
Cell Mol Neurobiol. 2017; 37(2):263-274 [PubMed] Related Publications
At present, many publications have evaluated the correlation between the DNA repair gene polymorphisms and glioma susceptibility. However, the results remain inconclusive. The aim of this research is to exhaustively assess the association of genetic polymorphisms in DNA repair genes with glioma risk in human. Meta-analysis method was conducted, and 33 studies with 15 SNPs in 9 genes were included (12553 glioma cases and 17178 controls). Correlation strength was evaluated by odds ratio with a 95 % confidence interval. Rs1799782 T allele and rs25487A allele might bring about higher risk of glioma in Asian population. Rs1805377 G allele was an increased risk genetic factor of glioma. Asian carried with rs3212986 A allele was more likely to have glioma. Rs1800067 G allele was a risk factor of developing glioma. Carriers with rs12917 CC genotype in MGMT gene had higher risk of glioma in Caucasian than other non-CC genotype carriers. Carriers with rs1136410 T allele in PARP1 gene could more likely to develop glioma in Caucasian. This meta-analysis suggests that glioma susceptibility is associated with rs1799782 and rs25487 of X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1), rs1805377 of XRCC4, rs1800067 of excision repair cross-complementing rodent repair deficiency complementation group 4 (ERCC4) and rs3212986 of ERCC1 in Asian population, and rs12917 of O-6-methylguanine-DNA methyltransferase (MGMT) and rs1136410 of poly(ADP-ribose) polymerase 1 (PARP1) in Caucasian population.

Makkoch J, Praianantathavorn K, Sopipong W, et al.
Genetic Variations in XRCC4 (rs1805377) and ATF6 (rs2070150) are not Associated with Hepatocellular Carcinoma in Thai Patients with Hepatitis B Virus Infection.
Asian Pac J Cancer Prev. 2016; 17(2):591-5 [PubMed] Related Publications
The liver is one of the most common sites of cancer in the world, hepatocellular carcinoma (HCC) predominating. Chronic hepatitis B virus infection (CHB) is considered as an important potential risk factors for HCC. Different people have diverse responses to HBV infection regarding the likelihood of HCC development, and host factors such as single nucleotide polymorphisms (SNPs) might account for this. The present study was conducted to evaluate any association between SNP frequencies in two genes, XRCC4 (rs1805377) and ATF6 (rs2070150), and the risk of CHB and HCC development in Thai patients. The study covered 369 subjects including 121 HCC patients, 141 with chronic hepatitis B virus infection (CHB) and 107 healthy controls. With TaqMan real-time PCR, the results showed that no significant association between XRCC4 (rs1805377) and ATF6 (rs2070150) and risk of HCC in the Thai population. From this first study of the 2 polymorphisms and HCC in Thailand it can concluded that rs1805377 and rs2070150 polymorphisms may not be applicable as genetic markers in the Thai population for HCC assessment.

Willis S, Villalobos VM, Gevaert O, et al.
Single Gene Prognostic Biomarkers in Ovarian Cancer: A Meta-Analysis.
PLoS One. 2016; 11(2):e0149183 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To discover novel prognostic biomarkers in ovarian serous carcinomas.
METHODS: A meta-analysis of all single genes probes in the TCGA and HAS ovarian cohorts was performed to identify possible biomarkers using Cox regression as a continuous variable for overall survival. Genes were ranked by p-value using Stouffer's method and selected for statistical significance with a false discovery rate (FDR) <.05 using the Benjamini-Hochberg method.
RESULTS: Twelve genes with high mRNA expression were prognostic of poor outcome with an FDR <.05 (AXL, APC, RAB11FIP5, C19orf2, CYBRD1, PINK1, LRRN3, AQP1, DES, XRCC4, BCHE, and ASAP3). Twenty genes with low mRNA expression were prognostic of poor outcome with an FDR <.05 (LRIG1, SLC33A1, NUCB2, POLD3, ESR2, GOLPH3, XBP1, PAXIP1, CYB561, POLA2, CDH1, GMNN, SLC37A4, FAM174B, AGR2, SDR39U1, MAGT1, GJB1, SDF2L1, and C9orf82).
CONCLUSION: A meta-analysis of all single genes identified thirty-two candidate biomarkers for their possible role in ovarian serous carcinoma. These genes can provide insight into the drivers or regulators of ovarian cancer and should be evaluated in future studies. Genes with high expression indicating poor outcome are possible therapeutic targets with known antagonists or inhibitors. Additionally, the genes could be combined into a prognostic multi-gene signature and tested in future ovarian cohorts.

Zhou C, Tang H, Yu J, et al.
Blood-based DNA methylation of DNA repair genes in the non-homologous end-joining (NEHJ) pathway in patient with glioma.
Int J Clin Exp Pathol. 2015; 8(8):9463-7 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: To investigate the blood-based DNA methylation of repair genes including LIG4, XRCC4, XRCC5, XRCC6 and XRCC7 that involved in non-homologous end-joining (NEHJ) DNA repair pathway in patients with glioma. Blood samples were obtained from 114 glioma patients, 96 normal controls, and 81 glioma patients after radiotherapy and chemotherapy. Blood-based DNA methylation of the five NHEJ repair genes was assayed by methylation-specific polymerase chain reaction (MSP). The DNA methylation level of XRCC5 and XRCC7 in glioma group are significantly higher than those of normal group (P<0.001). Moreover, radiotherapy treatment significantly increased methylation level of XRCC5 and XRCC7 compared to glioma group. No significant difference for the methylation of the other three genes, LIG4, XRCC4 and XRCC6 were detected among three groups.
IN CONCLUSION: our findings indicate that DNA methylation modification plays an important role to regulate the gene expression of XRCC5 and XRCC7, from the results that the gene methylation level of the glioma group is higher than that of the normal group. Increased methylation of XRCC5 and XRCC7 in blood samples of glioma patients and patients with radiotherapy and chemotherapy suggests that blood-based methylation level of XRCC5 and XRCC7 could be a potential indicator for evaluating of the effect of radiotherapy and chemotherapy for glioma patient.

Ding Y, Li LN
Association between single nucleotide polymorphisms of X-ray repair cross-complementing protein 4 gene and development of pancreatic cancer.
Genet Mol Res. 2015; 14(3):9626-32 [PubMed] Related Publications
We performed a study to evaluate X-ray repair cross-complementing protein 4 (XRCC4) gene polymorphisms and the development of pancreatic cancer. A case-control study including 206 patients with newly diagnosed primary pancreatic cancer and 412 controls was performed between January 2011 and October 2013 in a Chinese population. Genotypes of XRCC4 rs1805377, rs2075685, rs2075686 and rs1056503 were determined using polymerase chain reaction combined with a restriction fragment length polymorphism assay. Compared with controls, pancreatic cancer patients were more likely to have a higher body mass index, family history of cancer, and a habit of alcohol drinking compared with controls (P < 0.05). Logistic regression analysis showed that individuals carrying the TT genotype of XRCC4 rs2075685 had an increased risk of pancreatic cancer compared to those with the GG genotype, with an odds ratio (95% confidence interval) of 1.88 (1.15-3.08). Our results suggest that the XRCC4 rs2075685 polymorphism could influence the susceptibility to pancreatic cancer in a Chinese population.

Gan W, Liu P, Wei W
Akt promotes tumorigenesis in part through modulating genomic instability via phosphorylating XLF.
Nucleus. 2015; 6(4):261-5 [PubMed] Free Access to Full Article Related Publications
To maintain genome stability, mammalian cells have developed a delicate, yet efficient, system to sense and repair damaged DNA, including two evolutionarily conserved DNA damage repair (DDR) pathways: homologous recombination (HR) and non-homologous-end-joining (NHEJ). Deregulation in these repair pathways may lead to genomic instability and subsequent human diseases, including cancer. On the other hand, hyper-activation of the oncogenic Akt signaling pathway has been observed in almost all solid tumors. Emerging evidence has begun to reveal a possible role of active Akt in regulating DDR, possibly through suppression of HR. However, whether and how Akt regulates NHEJ remains largely undefined. To this end, we recently reported that Akt impairs NHEJ by phosphorylating XLF at T181, to trigger its dissociation from the functional DNA ligase IV (LIG4)/XRCC4 complex. Here, we provide an additional perspective discussing how Akt is activated upon DNA damage to regulate DNA repair pathways as well as the cellular apoptotic responses.

Yang HL, Qiao DD, Li K, et al.
Association of genetic polymorphisms in PRKDC and XRCC4 with risk of ESCC in a high-incidence region of North China.
Tumori. 2016 Mar-Apr; 102(2):131-4 [PubMed] Related Publications
BACKGROUND: The nonhomologous end-joining (NHEJ) pathway is the main mechanism repairing DNA double-strand breaks (DSBs) in human cells. This research was designed to study the association between selected variants in NHEJ members and esophageal squamous cell carcinoma (ESCC).
METHODS: Two single nucleotide polymorphisms (SNPs), PRKDC (rs7003908) and X-ray repair cross complementing group 4 (XRCC4; rs1805377), were genotyped in a total of 189 patients with ESCC and 189 unrelated control individuals in a high-risk area for ESCC in North China, and the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was applied.
RESULTS: A significantly different distribution was found in the frequency of PRKDC (rs7003908) genotype between the ESCC group and controls. Individuals homozygous for the C allele had a significant (3.185-fold) increased risk of ESCC. As for XRCC4 (rs1805377) polymorphism, no difference was found in distribution between the ESCC and control groups.
CONCLUSIONS: Our results suggest that variation in DNA repair genes may be associated with risk of ESCC.

Kabziński J, Majsterek I, Dziki A, Mik M
The Role of the XPF Gene Polymorphism (Xrcc4) Ser835ser in the Risk of Malignant Transformation of Cells in the Colorectal Cancer.
Pol Przegl Chir. 2015; 87(2):83-5 [PubMed] Related Publications
UNLABELLED: Participation of DNA repair systems in the pathogenesis of cancer has been a suspected phenomenon for a long time. Decreased efficiency in DNA repair translates to their ability to fix and consequently leads to mutations and the process of carcinogenesis. Linking individual polymorphisms of DNA repair systems with an increased risk of colorectal cancer will allow the classification of patients to high-risk groups and their placement under preventive program. The aim of the study was to determine the effect of XPF gene polymorphism Ser835Ser on increasing the risk of colorectal cancer in the Polish population.
MATERIAL AND METHODS: as the material blood collected from 146 patients diagnosed with colon cancer was used. The control group consisted of 149 healthy subjects. Genotyping was performed by Taq- Man method.
RESULTS: The results indicate that genotype TCC/TCT is associated with an decreased risk of colorectal cancer (OR 0.574; CI 95% 0.335-0.984; p=0.043).
CONCLUSIONS: Based on these results, we conclude that the XPF gene polymorphism Ser835Ser may be associated with a decreased risk of colorectal cancer.

Shen Q, Tian Y, Li K, et al.
Association of single nucleotide polymorphisms of DNA repair gene and susceptibility to pancreatic cancer.
Int J Clin Exp Pathol. 2015; 8(3):3180-5 [PubMed] Free Access to Full Article Related Publications
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.

Xu L, Tang H, El-Naggar AK, et al.
Genetic variants in DNA double-strand break repair genes and risk of salivary gland carcinoma: a case-control study.
PLoS One. 2015; 10(6):e0128753 [PubMed] Free Access to Full Article Related Publications
DNA double strand break (DSB) repair is the primary defense mechanism against ionizing radiation-induced DNA damage. Ionizing radiation is the only established risk factor for salivary gland carcinoma (SGC). We hypothesized that genetic variants in DSB repair genes contribute to individual variation in susceptibility to SGC. To test this hypothesis, we conducted a case-control study in which we analyzed 415 single nucleotide polymorphisms (SNPs) in 45 DSB repair genes in 352 SGC cases and 598 controls. Multivariate logistic regression analysis was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Rs3748522 in RAD52 and rs13180356 in XRCC4 were significantly associated with SGC after Bonferroni adjustment; ORs (95% CIs) for the variant alleles of these SNPs were 1.71 (1.40-2.09, P = 1.70 × 10(-7)) and 0.58 (0.45-0.74, P = 2.00 × 10(-5)) respectively. The genetic effects were modulated by histological subtype. The association of RAD52-rs3748522 with SGC was strongest for mucoepidermoid carcinoma (OR = 2.21, 95% CI: 1.55-3.15, P = 1.25 × 10(-5), n = 74), and the association of XRCC4-rs13180356 with SGC was strongest for adenoid cystic carcinoma (OR = 0.60, 95% CI: 0.42-0.87, P = 6.91 × 10(-3), n = 123). Gene-level association analysis revealed one gene, PRKDC, with a marginally significant association with SGC risk in non-Hispanic whites. To our knowledge, this study is the first to comprehensively evaluate the genetic effect of DSB repair genes on SGC risk. Our results indicate that genetic variants in the DSB repair pathways contribute to inter-individual differences in susceptibility to SGC and show that the impact of genetic variants differs by histological subtype. Independent studies are warranted to confirm these findings.

Chatterjee P, Choudhary GS, Alswillah T, et al.
The TMPRSS2-ERG Gene Fusion Blocks XRCC4-Mediated Nonhomologous End-Joining Repair and Radiosensitizes Prostate Cancer Cells to PARP Inhibition.
Mol Cancer Ther. 2015; 14(8):1896-906 [PubMed] Free Access to Full Article Related Publications
Exposure to genotoxic agents, such as ionizing radiation (IR), produces DNA damage, leading to DNA double-strand breaks (DSB); IR toxicity is augmented when the DNA repair is impaired. We reported that radiosensitization by a PARP inhibitor (PARPi) was highly prominent in prostate cancer cells expressing the TMPRSS2-ERG gene fusion protein. Here, we show that TMPRSS2-ERG blocks nonhomologous end-joining (NHEJ) DNA repair by inhibiting DNA-PKcs. VCaP cells, which harbor TMPRSS2-ERG and PC3 cells that stably express it, displayed γH2AX and 53BP1 foci constitutively, indicating persistent DNA damage that was absent if TMPRSS2-ERG was depleted by siRNA in VCaP cells. The extent of DNA damage was enhanced and associated with TMPRSS2-ERG's ability to inhibit DNA-PKcs function, as indicated by its own phosphorylation (Thr2609, Ser2056) and that of its substrate, Ser1778-53BP1. DNA-PKcs deficiency caused by TMPRSS2-ERG destabilized critical NHEJ components on chromatin. Thus, XRCC4 was not recruited to chromatin, with retention of other NHEJ core factors being reduced. DNA-PKcs autophosphorylation was restored to the level of parental cells when TMPRSS2-ERG was depleted by siRNA. Following IR, TMPRSS2-ERG-expressing PC3 cells had elevated Rad51 foci and homologous recombination (HR) activity, indicating that HR compensated for defective NHEJ in these cells, hence addressing why TMPRSS2-ERG alone did not lead to radiosensitization. However, the presence of TMPRSS2-ERG, by inhibiting NHEJ DNA repair, enhanced PARPi-mediated radiosensitization. IR in combination with PARPi resulted in enhanced DNA damage in TMPRSS2-ERG-expressing cells. Therefore, by inhibiting NHEJ, TMPRSS2-ERG provides a synthetic lethal interaction with PARPi in prostate cancer patients expressing TMPRSS2-ERG.

Su Y, Qi S, Dou C, et al.
Association of LIG4 and XRCC4 gene polymorphisms with the risk of human glioma in a Chinese population.
Int J Clin Exp Pathol. 2015; 8(2):2057-62 [PubMed] Free Access to Full Article Related Publications
We conducted a case-control study to assess the LIG4 and XRCC4 genes polymorphisms and development of glioma. A case-control study including 162 glioma cases and 324 controls was conducted in a Chinese population. Genotypes of rs10131 and rs1805388 in LIG4 and rs2075685 and rs1805377 in XRCC4 were conducted by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. Conditional logistic regression analysis showed that subjects carrying AA genotype of LIG4 rs10131 was associated with increased risk of glioma when compared with GG genotype, and the OR (95% CI) was 3.26 (1.50-7.23). We found that GA+AA of LIG4 rs10131 was associated with increased risk of glioma in those without family history of cancer, and the OR (95% CI) was 1.78 (1.12-2.83). However, no association was found between variants of LIG4 rs1805388, XRCC4 rs2075685 and XRCC4 rs1805377 and development of glioma. In conclusion, our results suggest that LIG4 rs10131 polymorphism in the DNA repair pathways plays an important role in the risk of glioma in a Chinese population.

Yang CH, Lin YD, Yen CY, et al.
A systematic gene-gene and gene-environment interaction analysis of DNA repair genes XRCC1, XRCC2, XRCC3, XRCC4, and oral cancer risk.
OMICS. 2015; 19(4):238-47 [PubMed] Related Publications
Oral cancer is the sixth most common cancer worldwide with a high mortality rate. Biomarkers that anticipate susceptibility, prognosis, or response to treatments are much needed. Oral cancer is a polygenic disease involving complex interactions among genetic and environmental factors, which require multifaceted analyses. Here, we examined in a dataset of 103 oral cancer cases and 98 controls from Taiwan the association between oral cancer risk and the DNA repair genes X-ray repair cross-complementing group (XRCCs) 1-4, and the environmental factors of smoking, alcohol drinking, and betel quid (BQ) chewing. We employed logistic regression, multifactor dimensionality reduction (MDR), and hierarchical interaction graphs for analyzing gene-gene (G×G) and gene-environment (G×E) interactions. We identified a significantly elevated risk of the XRCC2 rs2040639 heterozygous variant among smokers [adjusted odds ratio (OR) 3.7, 95% confidence interval (CI)=1.1-12.1] and alcohol drinkers [adjusted OR=5.7, 95% CI=1.4-23.2]. The best two-factor based G×G interaction of oral cancer included the XRCC1 rs1799782 and XRCC2 rs2040639 [OR=3.13, 95% CI=1.66-6.13]. For the G×E interaction, the estimated OR of oral cancer for two (drinking-BQ chewing), three (XRCC1-XRCC2-BQ chewing), four (XRCC1-XRCC2-age-BQ chewing), and five factors (XRCC1-XRCC2-age-drinking-BQ chewing) were 32.9 [95% CI=14.1-76.9], 31.0 [95% CI=14.0-64.7], 49.8 [95% CI=21.0-117.7] and 82.9 [95% CI=31.0-221.5], respectively. Taken together, the genotypes of XRCC1 rs1799782 and XRCC2 rs2040639 DNA repair genes appear to be significantly associated with oral cancer. These were enhanced by exposure to certain environmental factors. The observations presented here warrant further research in larger study samples to examine their relevance for routine clinical care in oncology.

Emami N, Saadat I, Omidvari S
Susceptibility to Colorectal Cancer and Two Genetic Polymorphisms of XRCC4.
Pathol Oncol Res. 2015; 21(4):881-5 [PubMed] Related Publications
The X-ray complementing group 4 (XRCC4, OMIM: 194363) plays a key role in non-homologous end-joining DNA repair pathway in mammalian cells. This pathway is believed to help maintain genomic stability. In the present study, it is hypothesized that genetic polymorphisms in the NHEJ repair XRCC4 gene may be associated with an increased risk in developing colorectal cancer (CRC). We genotyped two polymorphisms of XRCC4, G-1394T (rs6869366) and intron 3 insertion/deletion (I/D; rs28360071) in 200 colorectal cancer patients as well as 256 healthy individuals, and evaluated their association with CRC. We found that in G-1394T polymorphism, neither the TG nor the GG genotypes (versus the TT genotype) were associated with the risk of developing CRC. The results of our study indicate that in comparison with the II genotype, ID and DD genotypes had no significant association with the risk of developing CRC. Subjects with TT genotype and positive family history in colorectal cancer were found to be at a much lower risk of developing CRC in comparison with the reference group (OR = 0.31, 95%CI: 0.11-0.85, P =  .023). It should be noted that participants having at least one G allele (TG+GG genotypes) were at a significantly higher risk to develop the disease compared with the reference group (OR = 9.10, 95%CI: 2.00-41.3, P = 0.004). In relation to I/D polymorphism, among participants, those with positive family history, either with ID (OR =  .78, 95%CI: 2.26-10.0, P < 0.001) or DD genotypes (OR = 5.73, 95%CI: 1.99-16.4, P = 0.001) had a significantly association with the disease. Among participants with a positive family history in CRC, the haplotype GD dramatically increased the risk of developing CRC (OR = 10.2, 95%CI: 2.28-46, P = 0.002). The results of this study indicate that G-1394T and I/D polymorphisms of XRCC4 among individuals with positive family history for colorectal cancer substantially increase the risk factor for developing colorectal cancers.

Ming-Zhong S, Hui-Xiang J, Zhong-Wei Z, et al.
Genetic variants of the DNA damage repair genes XRCC4 and RAD51 are associated with susceptibility to esophageal cancer.
Clin Res Hepatol Gastroenterol. 2015; 39(3):379-83 [PubMed] Related Publications
OBJECTIVE: Altered DNA damage repair genes have been demonstrated to contribute to tumorigenesis. This study explored the relationship of genetic polymorphisms of the DNA repair genes XRCC4 and RAD51 to the risk of esophageal cancer.
METHODOLOGY: Genotyping of XRCC4 G-1394T (rs6869366) and RAD51-G135C by PCR-RFLP analysis was performed on 477 participants, of whom 219 were patients with esophageal cancer; the remaining participants were healthy. Statistical analysis, including Chi(2) test and logistic regression, was used to assess genotypic distributions and their correlation with cancer risk.
RESULTS: Carriers of the XRCC4 rs6869366 G allele (GT+GG) were at a significantly higher risk of esophageal cancer compared to individuals with the TT genotype [odds ratio (OR)=3.35, 95% confidence interval (CI): (1.16-10.24)]. Carriers of the C allele of RAD51 G135C (GC+CC) had a significantly increased risk of esophageal cancer compared to individuals with the GG genotype (OR=2.53, 95%CI: 1.15-6.70). Further, the variant genotypes of XRCC4 and RAD51 interacted to exacerbate the risk of esophageal cancer (OR=8.92, 95%CI: 2.47-38.20).
CONCLUSIONS: Variants of the DNA damage repair genes XRCC4 and RAD51 increase the risk of esophageal cancer.

Kim DH, Oh SY, Kim SY, et al.
DNA ligase4 as a prognostic marker in nasopharyngeal cancer patients treated with radiotherapy.
Asian Pac J Cancer Prev. 2014; 15(24):10985-9 [PubMed] Related Publications
BACKGROUND: The capability for DNA double-strand breaks (DSBs) repair is crucial for inherent radiosensitivity of tumor and normal cells. We have investigated the clinicopathologic significance of DNA repair gene expression in nasopharyngeal (NP) carcinoma.
MATERIALS AND METHODS: A total of 65 NP cancer patients who received radiotherapy were included. The immunopositivity to Ku 70, DNA-PKcs, MRN, RAD50, XRCC4, and LIG4 were examined in all tumor tissues.
RESULTS: The patients comprised 42 males and 23 females, with a median age of 56 years (range, 18-84). The expression levels of RAD50 (0,+1,+2,+3) were 27.7%, 32.3%, 21.5%, and 18.5%. LIG4 (±) were 43.1% and 56.9% respectively. The 5-year OS rate of patients with LIG4 (±) were 90% and 67.9%, respectively (p=0.035). The 5-year TTP rate of patients with LIG4 (±) were 75.9%, 55.5%, respectively (P=0.039).
CONCLUSIONS: Our results suggest the possibility of predicting the radiosensitivity of NP cancer by performing immunohistochemical analysis of LIG4.

Saadat M, Pashaei S, Amerizade F
Susceptibility to gastric cancer and polymorphisms of insertion/deletion at the intron 3 of the XRCC4 and VNTR at the promoter region of the XRCC5.
Pathol Oncol Res. 2015; 21(3):689-93 [PubMed] Related Publications
The genes encoding X-ray repair cross-complementing group 4 (XRCC4; OMIM: 194363) and 5 (XRCC5; OMIM: 194364) are involved in repair of DNA double-strand breaks. To investigating the associations between polymorphisms of Insertion/Deletion (I/D, rs28360071) in the intron 3 of the XRCC4 and VNTR in the promoter region of the XRCC5 and risk of gastric cancer, the present study was carried out. We included 159 (56 females, 103 males) with gastric cancer and 242 (75 females, 167 males) healthy blood donors frequency matched for age and gender. Using PCR-based methods, the genotypes of the study polymorphisms were determined. The alleles of VNTR XRCC5 polymorphism divided into two groups: L (0 and 1 repeats) and H (2 and 3 repeats) alleles. For the I/D XRCC4 polymorphism, after stratification of the subjects according to their family history (FH) of cancer, either the ID (OR = 3.19, 95%CI: 1.35-7.50, P = 0.008) or the DD genotypes (OR = 4.62, 95%CI: 1.63-13.0, P = 0.004) among positive FH persons, increased the risk of gastric cancer compared with the reference group (persons who have negative FH and II genotype). For the VNTR XRCC5 polymorphism, the LH + HH genotypes among positive FH persons, increased the risk of gastric cancer compared with the reference group (persons who have negative FH and LL genotype) (OR = 2.88, 95%CI: 1.34-6.18, P = 0.006). Sensitivity analysis showed that the above mentioned associations were not occurred due to the maldistribution of the genotypes among missing data. The present study suggests that both polymorphisms of the XRCC4 and XRCC5 might be risk factors for gastric cancer development especially among persons with positive FH.

Chen DB, Yang HJ
Comparison of gene regulatory networks of benign and malignant breast cancer samples with normal samples.
Genet Mol Res. 2014; 13(4):9453-62 [PubMed] Related Publications
The aim of this study was to explain the pathogenesis and deterioration process of breast cancer. Breast cancer expression profile data GSE27567 was downloaded from the Gene Expression Omnibus (GEO) database, and breast cancer-related genes were extracted from databases, including Cancer-Resource and Online Mendelian Inheritance In Man (OMIM). Next, h17 transcription factor data were obtained from the University of California, Santa Cruz. Database for Annotation, Visualization, and Integrated Discovery (DAVID)-enrichment analysis was applied and gene-regulatory networks were constructed by double-two-way t-tests in 3 states, including normal, benign, and malignant. Furthermore, network topological properties were compared between 2 states, and breast cancer-related bub genes were ranked according to their different degrees between each of the two states. A total of 2380 breast cancer-related genes and 215 transcription factors were screened by exploring databases; the genes were mainly enriched in their functions, such as cell apoptosis and proliferation, and pathways, such as p53 signaling and apoptosis, which were related with carcinogenesis. In addition, gene-regulatory networks in the 3 conditions were constructed. By comparing their network topological properties, we found that there is a larger transition of differences between malignant and benign breast cancer. Moreover, 8 hub genes (YBX1, ZFP36, YY1, XRCC5, XRCC4, ZFHX3, ZMAT3, and XPC) were identified in the top 10 genes ranked by different degrees. Through comparative analysis of gene-regulation networks, we identified the link between related genes and the pathogenesis of breast cancer. However, further experiments are needed to confirm our results.

He M, Hu X, Chen L, et al.
A recessive variant of XRCC4 predisposes to non- BRCA1/2 breast cancer in chinese women and impairs the DNA damage response via dysregulated nuclear localization.
Oncotarget. 2014; 5(23):12218-32 [PubMed] Free Access to Full Article Related Publications
XRCC4 plays a crucial role in the non-homologous end joining pathway that maintains genome stability. In this two-stage case-control study with 1,764 non-BRCA1/2 breast cancer patients and 1,623 cancer-free controls, we investigated the contribution of genetic variants of XRCC4 to breast cancer susceptibility in Chinese women. We identified a recessive missense variant, rs3734091 (c.739G>T, p.Ala247Ser), of XRCC4 that was significantly associated with an increased risk of breast cancer (odds ratio [OR] = 3.92, P = 0.007), particularly with the risk of developing triple-negative breast cancer (OR = 18.65, P < 0.0001). This p.Ala247Ser variant disturbed the nuclear localization of XRCC4 in cells homozygous for the rs3734091-T allele but not in heterozygous cells at both the cellular and tissue levels. In heterozygous cells, wild-type XRCC4 facilitated the nuclear localization of the XRCC4A247S mutant, thus compensating for the impaired localization of XRCC4A247S. This provided a biological mechanism by which rs3734091 conferred an increased susceptibility to non-BRCA1/2 breast cancer exclusively under a recessive model. Further functional analyses revealed that p.Ala247Ser impaired the DNA damage repair capacity and ultimately perturbed genomic stability. Taken together, our findings document the role of XRCC4 in non-BRCA1/2 breast cancer predisposition and reveal its underlying biological mechanism of action.

Yao JG, Huang XY, Long XD
Interaction of DNA repair gene polymorphisms and aflatoxin B1 in the risk of hepatocellular carcinoma.
Int J Clin Exp Pathol. 2014; 7(9):6231-44 [PubMed] Free Access to Full Article Related Publications
Aflatoxin B1 (AFB1) is an important environmental carcinogen and can induce DNA damage and involve in the carcinogenesis of hepatocellular carcinoma (HCC). The deficiency of DNA repair capacity related to the polymorphisms of DNA repair genes might play a central role in the process of HCC tumorigenesis. However, the interaction of DNA repair gene polymorphisms and AFB1 in the risk of hepatocellular carcinoma has not been elucidated. In this study, we investigated whether six polymorphisms (including rs25487, rs861539, rs7003908, rs28383151, rs13181, and rs2228001) in DNA repair genes (XPC, XRCC4, XRCC1, XRCC4, XPD, XRCC7, and XRCC3) interacted with AFB1, and the gene-environmental interactive role in the risk of HCC using hospital-based case-control study (including 1486 HCC cases and 1996 controls). Genotypes of DNA repair genes were tested using TaqMan-PCR technique. Higher AFB1 exposure was observed among HCC patients versus the control group [odds ratio (OR) = 2.08 for medium AFB1 exposure level and OR = 6.52 for high AFB1 exposure level]. Increasing risk of HCC was also observed in these with the mutants of DNA repair genes (risk values were from 1.57 to 5.86). Furthermore, these risk roles would be more noticeable under the conditions of two variables, and positive interactive effects were proved in the followed multiplicative interaction analysis. These results suggested that DNA repair risk genotypes might interact with AFB1 in the risk of HCC.

Guo H, Bassig BA, Lan Q, et al.
Polymorphisms in DNA repair genes, hair dye use, and the risk of non-Hodgkin lymphoma.
Cancer Causes Control. 2014; 25(10):1261-70 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Genetic polymorphisms in DNA repair genes and hair dye use may both have a role in the development of non-Hodgkin lymphoma (NHL). We aimed to examine the interaction between variants in DNA repair genes and hair dye use with risk of NHL in a population-based case-control study of Connecticut women.
METHODS: We examined 24 single nucleotide polymorphisms in 16 DNA repair genes among 518 NHL cases and 597 controls and evaluated the associations between hair dye use and risk of overall NHL and common NHL subtypes, stratified by genotype, using unconditional logistic regression.
RESULTS: Women who used hair dye before 1980 had a significantly increased risk of NHL, particularly for the follicular lymphoma (FL) subtype, but not for diffuse large B-cell lymphoma. The following genotypes in combination with hair dye use before 1980 were associated with FL risk: BRCA2 rs144848 AC+CC [odds ratio (OR) (95% confidence interval (CI)) 3.28(1.27-8.50)], WRN rs1346044 TT [OR(95% CI) 2.70(1.30-5.65)], XRCC3 rs861539 CT+TT [OR(95% CI) 2.76(1.32-5.77)], XRCC4 rs1805377 GG [OR(95% CI) 2.07(1.10-3.90)] and rs1056503 TT [OR(95% CI) 2.17(1.16-4.07)], ERCC1 rs3212961 CC [OR(95% CI) 1.93(1.00-3.72)], RAD23B rs1805329 CC [OR(95% CI) 2.28(1.12-4.64)], and MGMT rs12917 CC, rs2308321 AA, and rs2308327 AA genotypes [OR(95% CI) 1.96(1.06-3.63), 2.02(1.09-3.75), and 2.23(1.16-4.29), respectively]. In addition, a significant interaction with risk of overall NHL was observed between WRN rs1346044 and hair dye use before 1980 (p(interaction) = 0.032).
CONCLUSIONS: Our results indicated that genetic variation in DNA repair genes modifies susceptibility to NHL in relation to hair dye use, particularly for the FL subtype and in women who began using hair dye before 1980. Further studies are needed to confirm these observations.

Shao N, Li J, Xu B, et al.
Role of the functional variant (-652T>G) in the XRCC4 promoter in prostate cancer.
Mol Biol Rep. 2014; 41(11):7463-70 [PubMed] Related Publications
Several genes encoding DNA repair molecules have been proposed as cancer-susceptibility genes. Many studies have suggested that SNPs in XRCC4 could be implicated in altering the risk of prostate cancer (PCa). We examined the role of the functional variant (-652T>G) in the XRCC4 promoter in PCa. The transcriptional activity of XRCC4 gene was measured by luciferase assay. We performed real-time PCR/immunohistochemical assay to verify the association between expression level of XRCC4 mRNA/protein and XRCC4 -652T>G polymorphism. In addition, electrophoretic mobility shift assay (EMSA) was used to confirm whether this polymorphism has an effect on binding ability of the transcription factor. We found that the G variant significantly increased the transcription activity of the XRCC4 gene and the binding ability of transcriptional factor GATA-1 to the XRCC4 promoter. Furthermore, the results suggested that the XRCC4 protein and mRNA were overexpressed in individuals who carried the -652G allele compared to carriers of the -652T allele. In addition, the expression of XRCC4 in PCa tissues was lower than in adjacent normal tissues. Our data suggest that the XRCC4 promoter -652G>T polymorphism is functional and may influence genetic susceptibility to prostate cancer. Case-control studies are required to validate our findings in the future.

Esteban-Jurado C, Vila-Casadesús M, Garre P, et al.
Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer.
Genet Med. 2015; 17(2):131-42 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Colorectal cancer is an important cause of mortality in the developed world. Hereditary forms are due to germ-line mutations in APC, MUTYH, and the mismatch repair genes, but many cases present familial aggregation but an unknown inherited cause. The hypothesis of rare high-penetrance mutations in new genes is a likely explanation for the underlying predisposition in some of these familial cases.
METHODS: Exome sequencing was performed in 43 patients with colorectal cancer from 29 families with strong disease aggregation without mutations in known hereditary colorectal cancer genes. Data analysis selected only very rare variants (0-0.1%), producing a putative loss of function and located in genes with a role compatible with cancer. Variants in genes previously involved in hereditary colorectal cancer or nearby previous colorectal cancer genome-wide association study hits were also chosen.
RESULTS: Twenty-eight final candidate variants were selected and validated by Sanger sequencing. Correct family segregation and somatic studies were used to categorize the most interesting variants in CDKN1B, XRCC4, EPHX1, NFKBIZ, SMARCA4, and BARD1.
CONCLUSION: We identified new potential colorectal cancer predisposition variants in genes that have a role in cancer predisposition and are involved in DNA repair and the cell cycle, which supports their putative involvement in germ-line predisposition to this neoplasm.

Hornhardt S, Rößler U, Sauter W, et al.
Genetic factors in individual radiation sensitivity.
DNA Repair (Amst). 2014; 16:54-65 [PubMed] Related Publications
Cancer risk and radiation sensitivity are often associated with alterations in DNA repair, cell cycle, or apoptotic pathways. Interindividual variability in mutagen or radiation sensitivity and in cancer susceptibility may also be traced back to polymorphisms of genes affecting e.g. DNA repair capacity. We studied possible associations between 70 polymorphisms of 12 DNA repair genes with basal and initial DNA damage and with repair thereof. We investigated DNA damage induced by ionizing radiation in lymphocytes isolated from 177 young lung cancer patients and 169 cancer-free controls. We also sought replication of our findings in an independent sample of 175 families (in total 798 individuals). DNA damage was assessed by the Olive tail moment (OTM) of the comet assay. DNA repair capacity (DRC) was determined for 10, 30 and, 60min of repair. Genes involved in the single-strand-repair pathway (SSR; like XRCC1 and MSH2) as well as genes involved in the double-strand-repair pathway (DSR; like RAD50, XRCC4, MRE11 and ATM) were found to be associated with DNA damage. The most significant association was observed for marker rs3213334 (p=0.005) of XRCC1 with basal DNA damage (B), in both cases and controls. A clear additive effect on the logarithm of OTM was identified for the marker rs1001581 of the same LD-block (p=0.039): BCC=-1.06 (95%-CI: -1.16 to -0.96), BCT=-1.02 (95%-CI: -1.11 to -0.93) and BTT=-0.85 (95%-CI: -1.01 to -0.68). In both cases and controls, we observed significantly higher DNA basal damage (p=0.007) for carriers of the genotype AA of marker rs2237060 of RAD50 (involved in DSR). However, this could not be replicated in the sample of families (p=0.781). An alteration to DRC after 30min of repair with respect to cases was observed as borderline significant for marker rs611646 of ATM (involved in DSR; p=0.055), but was the most significant finding in the sample of families (p=0.009). Our data indicate that gene variation impacts measurably on DNA damage and repair, suggesting at least a partial contribution to radiation sensitivity and lung cancer susceptibility.

Andrew AS, Gui J, Hu T, et al.
Genetic polymorphisms modify bladder cancer recurrence and survival in a USA population-based prognostic study.
BJU Int. 2015; 115(2):238-47 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To identify genetic variants that modify bladder cancer prognosis focusing on genes involved in major biological carcinogenesis processes (apoptosis, proliferation, DNA repair, hormone regulation, immune surveillance, and cellular metabolism), as nearly half of patients with bladder cancer experience recurrences reliable predictors of this recurrent phenotype are needed to guide surveillance and treatment.
PATIENTS AND METHODS: We analysed variant genotypes hypothesised to modify these processes in 563 patients with urothelial-cell carcinoma enrolled in a population-based study of incident bladder cancer conducted in New Hampshire, USA. After diagnosis, patients were followed over time to ascertain recurrence and survival status, making this one of the first population-based studies with detailed prognosis data. Cox proportional hazards regression was used to assess the relationship between single nucleotide polymorphisms (SNPs) and prognosis endpoints.
RESULTS: Patients with aldehyde dehydrogenase 2 (ALDH2) variants had a shorter time to first recurrence (adjusted non-invasive hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.29-2.78). There was longer survival among patients with non-invasive tumours associated with DNA repair X-ray repair cross-complementing protein 4 (XRCC4) heterozygous genotype compared with wild-type (adjusted HR 0.53, 95% CI 0.38-0.74). Time to recurrence was shorter for patients who had a variant allele in vascular cellular adhesion molecule 1 (VCAM1) and were treated with immunotherapy (P interaction < 0.001).
CONCLUSIONS: Our analysis suggests candidate prognostic SNPs that could guide personalised bladder cancer surveillance and treatment.

Lin ZH, Chen JC, Wang YS, et al.
DNA repair gene XRCC4 codon 247 polymorphism modified diffusely infiltrating astrocytoma risk and prognosis.
Int J Mol Sci. 2013; 15(1):250-60 [PubMed] Free Access to Full Article Related Publications
The DNA repair gene X-ray cross-complementary group 4 (XRCC4), an important caretaker of the overall genome stability, is thought to play a major role in human tumorigenesis. We investigated the association between an important polymorphic variant of this gene at codon 247 (rs373409) and diffusely infiltrating astrocytoma (DIA) risk and prognosis. This hospital-based case-control study investigated this association in the Guangxi population. In total, 242 cases with DIA and 358 age-, sex-, and race-matched healthy controls were genotyped using TaqMan-PCR technique. We found a significant difference in the frequency of XRCC4 genotypes between cases and controls. Compared with the homozygote of XRCC4 codon 247 Ala alleles (XRCC4-AA), the genotypes of XRCC4 codon 247 Ser alleles (namely XRCC4-AS or -SS) increased DIA risk (odds ratios [OR], 1.82 and 2.89, respectively). Furthermore, XRCC4 polymorphism was correlated with tumor dedifferentiation of DIA (r = 0.261, p < 0.01). Additionally, this polymorphism modified the overall survival of DIA patients (the median survival times were 26, 14, and 8 months for patients with XRCC4-AA, -AS, and -SS, respectively). Like tumor grade, XRCC4 codon 247 polymorphism was an independent prognostic factor influencing the survival of DIA. These results suggest that XRCC4 codon 247 polymorphism may be associated with DIA risk and prognosis among the Guangxi population.

Wu HC, Delgado-Cruzata L, Machella N, et al.
DNA double-strand break repair genotype and phenotype and breast cancer risk within sisters from the New York site of the Breast Cancer Family Registry (BCFR).
Cancer Causes Control. 2013; 24(12):2157-68 [PubMed] Free Access to Full Article Related Publications
PURPOSE: We previously observed that poor DNA repair phenotype is associated with increased breast cancer (BC) risk within families. Here, we examined whether genetic variation in double-strand break repair (DSBR) genes is associated with BC risk and if genotypes are related to phenotype in unaffected women.
METHODS: Using data from the New York site of the Breast Cancer Family Registry, we investigated 25 single-nucleotide polymorphism (SNPs) involved in DSBR using biospecimens from 337 BC cases and 410 unaffected sister controls.
RESULTS: Genotypes in XRCC4 were associated with BC risk, with ORs of 1.67 (95 % CI 1.01-2.76) for the combined GA/AA of rs1805377 and 1.69 (95 % CI 1.03-2.77) for rs1056503 TG/GG; these associations were no longer statistically significant in multivariable conditional logistic regression models. When examining the association of SNPs with phenotype, we found that genotypes of XRCC5 rs3834 and rs1051685, which were highly correlated with each other, were associated with end-joining (EJ) capacity; women with the XRCC5 rs3834 GA genotype had better DNA repair as measured by higher levels of EJ capacity (37.8 ± 14.1 % for GA vs. 27.9 ± 11.8 % for GG carriers p = 0.0006). Women with the AA genotype of BRCA1 rs799917 also had higher EJ capacity (35.1 ± 9.2 %) than those with GG (26.4 ± 10.1 %, p = 0.02).
CONCLUSIONS: Overall, we found that selected DSBR genotypes were associated with phenotype, although they were not associated with BC risk itself, suggesting that phenotypic measures are influenced by endogenous and exogenous factors across the life course and may be better markers than genotypic measures for ascertaining BC risk.

He F, Chang SC, Wallar GM, et al.
Association of XRCC3 and XRCC4 gene polymorphisms, family history of cancer and tobacco smoking with non-small-cell lung cancer in a Chinese population: a case-control study.
J Hum Genet. 2013; 58(10):679-85 [PubMed] Free Access to Full Article Related Publications
Single-nucleotide polymorphisms (SNPs) of DNA repair genes have been reported to modify cancer risk. This study aimed to determine SNPs of the DNA repair genes X-ray repair cross-complementing group 3 (XRCC3) and X-ray cross-complementing group 4 (XRCC4) and their association with non-small-cell lung cancer (NSCLC) susceptibility in a Chinese population. A total of 507 NSCLC patients and 662 healthy controls were recruited for genotyping. Epidemiological and clinical data were also collected for association studies. The data showed that the rs1799794 G allele in the XRCC3 gene and minor allele carriers of XRCC4, including rs1056503 and rs9293337, were inversely associated with NSCLC risk (GG vs homozygote AA), whereas the rs861537 AG or AA genotype and XRCC4 rs6869366 had a significantly increased NSCLC risk. Furthermore, tobacco smoking over 26 pack-years, a family history of lung cancer, exposure to environmental tobacco smoke (ETS) and negative mental status were risk factors for developing NSCLC. This study suggests that SNPs of XRCC3 and XRCC4 and other environmental factors are risk factors for developing NSCLC in this Chinese Han population.

Long XD, Zhao D, Wang C, et al.
Genetic polymorphisms in DNA repair genes XRCC4 and XRCC5 and aflatoxin B1-related hepatocellular carcinoma.
Epidemiology. 2013; 24(5):671-81 [PubMed] Related Publications
BACKGROUND: Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity and may play an important role in carcinogenesis. We investigated the role of genetic polymorphisms at XRCC4 codon 247 (rs3734091, XRCC4P) and XRCC5 codon 180 (rs80309960, XRCC5P) in liver cancer (hepatocellular carcinoma) caused by aflatoxin B1 (AFB1).
METHODS: A hospital-based case-control study, including 1499 liver cancer cases and 2045 controls without any liver disease, was conducted in a high aflatoxin exposure area in the Guangxi region of China to assess the relationship between these two polymorphisms and aflatoxin-related liver cancer risk and prognosis. Genotypes, mRNA levels, and the hot-spot mutation of TP53 gene (TP53M) related to AFB1 exposure was tested using TaqMan-PCR technique. XRCC4 protein level was analyzed by immunohistochemistry.
RESULTS: For XRCC4P and XRCC5P, only XRCC4P modified liver cancer risk. Compared with the homozygote of XRCC4 codon 247 Ala alleles (XRCC4-AA), the genotypes of XRCC4 codon 247 Ser alleles (namely XRCC4-AS or -SS) increased liver cancer risk (odds ratio [OR] = 1.35 and 2.02, respectively). Significant interactive effects between risk genotypes (OR > 1) and aflatoxin exposure status were also observed in the joint effects analysis. Moreover, this polymorphism was associated not only with lower XRCC4 expression levels but also with higher AFB1-DNA adduct levels and increasing TP53M and portal vein tumor risk. Additionally, XRCC4P modified the recurrence-free survival and overall survival of cases, especially under conditions of high aflatoxin exposure.
CONCLUSION: XRCC4P may be a genetic modifier for the risk and outcome of hepatocellular carcinoma induced by AFB1 exposure.

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