ERCC3

Gene Summary

Gene:ERCC3; excision repair cross-complementation group 3
Aliases: XPB, BTF2, TTD2, GTF2H, RAD25, TFIIH
Location:2q21
Summary:This gene encodes an ATP-dependent DNA helicase that functions in nucleotide excision repair. The encoded protein is a subunit of basal transcription factor 2 (TFIIH) and, therefore, also functions in class II transcription. Mutations in this gene are associated with Xeroderma pigmentosum B, Cockayne's syndrome, and trichothiodystrophy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:TFIIH basal transcription factor complex helicase XPB subunit
HPRD
Source:NCBIAccessed: 17 August, 2015

Ontology:

What does this gene/protein do?
Show (48)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 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.

  • Drosophila Proteins
  • Xeroderma Pigmentosum Group A Protein
  • Cockayne Syndrome
  • Endonucleases
  • Childhood Cancer
  • DNA Repair
  • Adolescents
  • DNA Repair Enzymes
  • Transcription Factor TFIIH
  • Molecular Sequence Data
  • Polymerase Chain Reaction
  • Ultraviolet Rays
  • Base Sequence
  • Mutation
  • Cisplatin
  • Messenger RNA
  • Sequence Homology
  • Genetic Predisposition
  • Chromosome 2
  • Single Nucleotide Polymorphism
  • Transcription
  • Transcription Factors
  • Amino Acid Sequence
  • RTPCR
  • Transcription Factors, TFII
  • Regression Analysis
  • Risk Factors
  • DNA-Binding Proteins
  • Genetic Complementation Test
  • Gene Expression
  • Smoking
  • Cancer Gene Expression Regulation
  • Case-Control Studies
  • DNA Helicases
  • Nuclear Proteins
  • Xeroderma Pigmentosum
  • Survival Rate
  • Genotype
  • Tumor Markers
  • Skin Cancer
Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

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: ERCC3 (cancer-related)

Alekseev S, Coin F
Orchestral maneuvers at the damaged sites in nucleotide excision repair.
Cell Mol Life Sci. 2015; 72(11):2177-86 [PubMed] Related Publications
To safeguard the genome from the accumulation of deleterious effects arising from DNA lesions, cells developed several DNA repair mechanisms that remove specific types of damage from the genome. Among them, Nucleotide Excision Repair (NER) is unique in its ability to remove a very broad spectrum of lesions, the most important of which include UV-induced damage, bulky chemical adducts and some forms of oxidative damage. Two sub-pathways exist in NER; Transcription-Coupled Repair (TC-NER) removes lesion localized exclusively in transcribed genes while Global Genome Repair (GG-NER) removes lesions elsewhere. In TC- or GG-NER, more than 30 proteins detect, open, incise and resynthesize DNA. Intriguingly, half of them are involved in the detection of DNA damage, implying that this is a crucial repair step requiring a high level of regulation. We review here the complex damage recognition step of GG-NER with a focus on post-translational modifications that help the comings and goings of several protein complexes on the same short damaged DNA locus.

Singh A, Compe E, Le May N, Egly JM
TFIIH subunit alterations causing xeroderma pigmentosum and trichothiodystrophy specifically disturb several steps during transcription.
Am J Hum Genet. 2015; 96(2):194-207 [PubMed] Free Access to Full Article Related Publications
Mutations in genes encoding the ERCC3 (XPB), ERCC2 (XPD), and GTF2H5 (p8 or TTD-A) subunits of the transcription and DNA-repair factor TFIIH lead to three autosomal-recessive disorders: xeroderma pigmentosum (XP), XP associated with Cockayne syndrome (XP/CS), and trichothiodystrophy (TTD). Although these diseases were originally associated with defects in DNA repair, transcription deficiencies might be also implicated. By using retinoic acid receptor beta isoform 2 (RARB2) as a model in several cells bearing mutations in genes encoding TFIIH subunits, we observed that (1) the recruitment of the TFIIH complex was altered at the activated RARB2 promoter, (2) TFIIH participated in the recruitment of nucleotide excision repair (NER) factors during transcription in a manner different from that observed during NER, and (3) the different TFIIH variants disturbed transcription by having distinct consequences on post-translational modifications of histones, DNA-break induction, DNA demethylation, and gene-loop formation. The transition from heterochromatin to euchromatin was disrupted depending on the variant, illustrating the fact that TFIIH, by contributing to NER factor recruitment, orchestrates chromatin remodeling. The subtle transcriptional differences found between various TFIIH variants thus participate in the phenotypic variability observed among XP, XP/CS, and TTD individuals.

Zhou J, Liu ZY, Li CB, et al.
Genetic polymorphisms of DNA repair pathways influence the response to chemotherapy and overall survival of gastric cancer.
Tumour Biol. 2015; 36(4):3017-23 [PubMed] Related Publications
We aimed to evaluate the clinical response to platinum-based chemotherapy and treatment outcome of gastric cancer patients in the present of ERCC1, ERCC2, NBN, RAD51, and XRCC3 gene polymorphisms. A number of 415 patients of gastric cancer that received platinum-based chemotherapy were enrolled in the present study. The presence of ERCC1 rs11615 and rs2298881, ERCC2 rs1799793 and rs13181, NBN rs1805794, rs709816, and RAD51 rs1801321 and XRCC3 rs1799794 were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Conditional regression analysis identified that CC genotype of ERCC1 rs11615 and AA genotype of ERCC2 rs1799793 was associated with a better response to chemotherapy in gastric cancer patients, and the odds ratio (ORs)(95% confidence interval (CI)) were 2.70(1.33-5.70) and 3.12(1.52-6.84), respectively. By the Cox analysis, the CC genotype of ERCC1 rs11615, AA genotype of ERCC2 rs1799793, and CC genotype of NBN rs1805794 were significantly associated with a longer overall survival (OS) of gastric cancer. In conclusion, our results suggest that ERCC1 rs11615, ERCC2 rs1799793, and NBN rs1805794 polymorphisms in the DNA repair pathways may influence the response to chemotherapy and OS of gastric cancer.

Henríquez-Hernández LA, Valenciano A, Foro-Arnalot P, et al.
Single nucleotide polymorphisms in DNA repair genes as risk factors associated to prostate cancer progression.
BMC Med Genet. 2014; 15:143 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Besides serum levels of PSA, there is a lack of prostate cancer specific biomarkers. It is need to develop new biological markers associated with the tumor behavior which would be valuable to better individualize treatment. The aim of this study was to elucidate the relationship between single nucleotide polymorphisms (SNPs) in genes involved in DNA repair and prostate cancer progression.
METHODS: A total of 494 prostate cancer patients from a Spanish multicenter study were genotyped for 10 SNPs in XRCC1, ERCC2, ERCC1, LIG4, ATM and TP53 genes. The SNP genotyping was made in a Biotrove OpenArray® NT Cycler. Clinical tumor stage, diagnostic PSA serum levels, and Gleason score at diagnosis were obtained for all participants. Genotypic and allelic frequencies were determined using the web-based environment SNPator.
RESULTS: SNPs rs11615 (ERCC1) and rs17503908 (ATM) appeared as risk factors for prostate cancer aggressiveness. Patients wild homozygous for these SNPs (AA and TT, respectively) were at higher risk for developing cT2b - cT4 (OR = 2.21 (confidence interval (CI) 95% 1.47 - 3.31), p < 0.001) and Gleason scores ≥ 7 (OR = 2.22 (CI 95% 1.38 - 3.57), p < 0.001), respectively. Moreover, those patients wild homozygous for both SNPs had the greatest risk of presenting D'Amico high-risk tumors (OR = 2.57 (CI 95% 1.28 - 5.16)).
CONCLUSIONS: Genetic variants at DNA repair genes are associated with prostate cancer progression, and would be taken into account when assessing the malignancy of prostate cancer.

Zhou JY, He LW, Liu J, et al.
Comprehensive assessment of associations between ERCC2 Lys751Gln/Asp312Asn polymorphisms and risk of non- Hodgkin lymphoma.
Asian Pac J Cancer Prev. 2014; 15(21):9347-53 [PubMed] Related Publications
BACKGROUND: Excision repair crossing-complementing group 2 (ERCC2), also called xeroderma pigmentosum complementary group D (XPD), plays a crucial role in the nucleotide excision repair (NER) pathway. Previous epidemiological studies have reported associations between ERCC2 polymorphisms and non-Hodgkin lymphoma (NHL) risk, but the results have remained controversial.
MATERIALS AND METHODS: We conducted this meta- analysis based on eligible case-control studies to investigate the role of two ERCC2 polymorphisms (Lys751Gln and Asp312Asn) in determining susceptibility to NHL. Ten case-control studies from several electronic databases were included in our study up to August 14, 2014. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed- or random-effects models to estimate the association strength.
RESULTS: The combined results based on all studies did not show any association between Lys751Gln/Asp312Asn polymorphisms and NHL risk for all genetic models. Stratified analyses by histological subtype and ethnicity did not indicate any significant association between Lys751Gln polymorphism and NHL risk. However, a significant reduced risk of NHL was found among population-based studies (Lys/Gln versus Lys/Lys: OR=0.87, 95% CI=0.77-0.99, P=0.037) but not hospital-based studies. As for Asp312Asn polymorphism, there was no evidence for the association between this polymorphism and the risk of NHL in all subgroup analyses.
CONCLUSIONS: This meta-analysis suggests that there may be no association between Lys751Gln/Asp312Asn polymorphism and the risk of NHL and its two subtypes, whereas ERCC2 Lys751Gln heterozygote genotype may provide protective effects against the risk of NHL in population-based studies. Therefore, large-scale and well-designed studies are needed to clarify the effects of haplotypes, gene-gene, and gene-environment interactions on these polymorphisms and the risk of NHL and its different histological subtypes in an ethnicity specific population.

Wu KG, He XF, Li YH, et al.
Association between the XPD/ERCC2 Lys751Gln polymorphism and risk of cancer: evidence from 224 case-control studies.
Tumour Biol. 2014; 35(11):11243-59 [PubMed] Related Publications
Genetic variations in the xeroderma pigmentosum group D (XPD) gene may increase cancer susceptibility by affecting the capacity for DNA repair. A lot of studies have reported the association of XPD Lys751Gln polymorphism with risk of cancer, but the results remained controversial. Hence, we performed a systematic review and conducted a meta-analysis to explore association of the XPD Lys751Gln polymorphism with risk of cancer (78,398 cases and 103,178 controls from 224 studies). Overall, a significantly increased cancer risk was found in all genetic models (dominant model: odds ratio (OR) = 1.10, 95% confidence interval (CI) = 1.06-1.14; recessive model: OR = 1.10, 95% CI = 1.05-1.15; homozygous model: OR = 1.14, 95% CI = 1.08-1.21; heterozygous model: OR = 1.09, 95% CI = 1.05-1.12; additive model: OR = 1.08, 95% CI= 1.05-1.11) when all eligible studies were pooled into the meta-analysis. In further stratified and sensitivity analyses, the elevated risk of cancer remained for subgroups of breast cancer, esophageal cancer, hepatocellular cancer, leukemia, lung cancer, and melanoma. In summary, this meta-analysis suggests the XPD Lys751Gln polymorphism is a genetic susceptibility for some cancer types. Moreover, ethnicity, histological type of cancer, and smokers seem to contribute to varying expressions of the Lys751Gln on some cancer risk. In addition, our work also points out the importance of new studies for Lys751Gln association in endometrial cancer and ovarian cancer, where at least some of the covariates responsible for heterogeneity could be controlled, to obtain a more conclusive understanding about the function of the Lys751Gln polymorphism in cancer development.

Ramaniuk VP, Nikitchenko NV, Savina NV, et al.
Polymorphism of DNA repair genes OGG1, XRCC1, XPD and ERCC6 in bladder cancer in Belarus.
Biomarkers. 2014; 19(6):509-16 [PubMed] Related Publications
CONTEXT: The study of DNA base and nucleotide excision repair gene polymorphisms in bladder cancer seems to have a predictive value because of the evident relationship between the DNA damage response induced by environmental mutagens and cancer predisposition.
OBJECTIVE: The objective was to determine OGG1 Ser326Cys, XRCC1 Arg399Gln, XPD Asp312Asn, and ERCC6 Met1097Val polymorphisms in bladder cancer patients as compared to controls.
METHODS: Both groups were predominantly represented by Belarusians and Eastern Slavs. DNA samples from 336 patients and 370 controls were genotyped using a PCR-RFLP method.
RESULTS: The genotype distributions were in agreement with the Hardy-Weinberg equilibrium. The minor allele frequencies in the control population were in the range of those in Caucasians in contrast to Asians. The OGG1 326 Ser/Cys and XPD 312 Asp/Asn heterozygous genotypes were inversely associated with cancer risk (OR [95% CI] = 0.69 [0.50-0.95] and 1.35 [1.0-1.82], respectively). The contrasting effects of these genotypes were potentiated due to their interactions with smoking habit or age.
CONCLUSIONS: Among four DNA repair gene polymorphisms, the OGG1 326 Ser/Cys and XPD 312 Asp/Asn heterozygous genotypes might be recognized as potential genetic markers modifying susceptibility to bladder cancer in Belarus.

Sullivan I, Salazar J, Majem M, et al.
Pharmacogenetics of the DNA repair pathways in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy.
Cancer Lett. 2014; 353(2):160-6 [PubMed] Related Publications
Genetic variants in DNA repair genes may play a role in the effectiveness of platinum-based chemotherapy in non-small cell lung cancer (NSCLC). We analyzed 17 SNPs in eight genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, XPA, XRCC1 and XRCC2) involved in DNA repair mechanisms and its association with outcome in NSCLC. This prospective study included patients with stages III and IV treated with platinum-based chemotherapy. All patients (n = 161) received cisplatin or carboplatin plus a third-generation drug. Additionally, stage IIIA and IIIB patients (n = 74) received concomitant or sequential radiotherapy. Germline polymorphisms were analyzed using the BioMark system in blood DNA samples. We found that in stage III patients, response was significantly associated with SNPs in ERCC1 and in ERCC3 genes, while radiotherapy-derived toxicity correlated with SNPs in the ERCC2 gene. In stage IV patients, response was associated with a genetic variant in the ERCC4 gene and survival with a SNP in the XRCC1 gene. The complexity of the DNA repair mechanisms along with the heterogeneity in the treatment of lung cancer could explain the role of multiple genes as putative biomarkers of patient outcome.

Kelso TW, Baumgart K, Eickhoff J, et al.
Cyclin-dependent kinase 7 controls mRNA synthesis by affecting stability of preinitiation complexes, leading to altered gene expression, cell cycle progression, and survival of tumor cells.
Mol Cell Biol. 2014; 34(19):3675-88 [PubMed] Free Access to Full Article Related Publications
Cyclin-dependent kinase 7 (CDK7) activates cell cycle CDKs and is a member of the general transcription factor TFIIH. Although there is substantial evidence for an active role of CDK7 in mRNA synthesis and associated processes, the degree of its influence on global and gene-specific transcription in mammalian species is unclear. In the current study, we utilize two novel inhibitors with high specificity for CDK7 to demonstrate a restricted but robust impact of CDK7 on gene transcription in vivo and in in vitro-reconstituted reactions. We distinguish between relative low- and high-dose responses and relate them to distinct molecular mechanisms and altered physiological responses. Low inhibitor doses cause rapid clearance of paused RNA polymerase II (RNAPII) molecules and sufficed to cause genome-wide alterations in gene expression, delays in cell cycle progression at both the G1/S and G2/M checkpoints, and diminished survival of human tumor cells. Higher doses and prolonged inhibition led to strong reductions in RNAPII carboxyl-terminal domain (CTD) phosphorylation, eventual activation of the p53 program, and increased cell death. Together, our data reason for a quantitative contribution of CDK7 to mRNA synthesis, which is critical for cellular homeostasis.

Chiang CI, Huang YL, Chen WJ, et al.
XRCC1 Arg194Trp and Arg399Gln polymorphisms and arsenic methylation capacity are associated with urothelial carcinoma.
Toxicol Appl Pharmacol. 2014; 279(3):373-9 [PubMed] Related Publications
The association between DNA repair gene polymorphisms and bladder cancer has been widely studied. However, few studies have examined the correlation between urothelial carcinoma (UC) and arsenic or its metabolites. The aim of this study was to examine the association between polymorphisms of the DNA repair genes, XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln, with urinary arsenic profiles and UC. To this end, we conducted a hospital-based case-control study with 324 UC patients and 647 age- and gender-matched non-cancer controls. Genomic DNA was used to examine the genotype of XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln by PCR-restriction fragment length polymorphism analysis (PCR-RFLP). Urinary arsenic profiles were measured by high performance liquid chromatography (HPLC) linked with hydride generator and atomic absorption spectrometry. The XRCC1 399 Gln/Gln and 194 Arg/Trp and Trp/Trp genotypes were significantly related to UC, and the odds ratio (OR) and 95% confidence interval (95%CI) were 1.68 (1.03-2.75) and 0.66 (0.48-0.90), respectively. Participants with higher total urinary arsenic levels, a higher percentage of inorganic arsenic (InAs%) and a lower percentage of dimethylarsinic acid (DMA%) had a higher OR of UC. Participants carrying XRCC1 risk diplotypes G-C/G-C, A-C/A-C, and A-T/G-T, and who had higher total arsenic levels, higher InAs%, or lower DMA% compared to those with other XRCC1 diplotypes had a higher OR of UC. Our results suggest that the XRCC1 399 Gln/Gln and 194 Arg/Arg DNA repair genes play an important role in poor arsenic methylation capacity, thereby increasing the risk of UC in non-obvious arsenic exposure areas.

Huang LM, Shi X, Yan DF, et al.
Association between ERCC2 polymorphisms and glioma risk: a meta-analysis.
Asian Pac J Cancer Prev. 2014; 15(11):4417-22 [PubMed] Related Publications
ERCC2 is an essential component of the nucleotide excision repair pathway which is involved in the effective maintenance of genome integrity. Association studies on ERCC2 polymorphisms and glioma risk have yielded inconclusive results. This meta-analysis was performed to gain a better insight into the relationship between ERCC2 polymorphisms and glioma risk. A systematic literature search updated to December 2, 2013 was performed in the Pubmed and EMBASE databases. Crude pooled odds ratios (ORs) with their corresponding 95% confidence intervals (95% CIs) were used to estimate the association between ERCC2 polymorphisms and glioma risk under a suitable effect model according to heterogeneity. All analyses were performed using Review Manager 5 (version 5.2) and STATA (version 12.0). The combined results demonstrated rs13181 to be significantly associated with glioma risk (G allele versus T allele: OR=1.15, 95% CI=1.05-1.26, P=0.002; dominant model: OR=1.22, 95% CI=1.07-1.39, P=0.002; recessive model: OR=1.18, 95% CI=0.98-1.41, P=0.070). We also found that rs13181 acts in an allele dose-dependent manner (GG versus TT: OR=1.30, 95% CI=1.07-1.57, P=0.009; TG versus TT: OR=1.20, 95%=CI 1.05-1.37, P=0.009; trend test, P=0.004). However, no evidence was found in analyses for the association between other 3 ERCC2 polymorphisms (rs238406, rs1799793, and rs1052555) and susceptibility to glioma development. Our meta-analysis suggests that rs13181 is significantly associated with glioma risk in an allele dose-dependent manner, whereas, 3 other ERCC2 polymorphisms (rs238406, rs1799793, and rs1052555) may have no influence.

Bănescu C, Trifa AP, Demian S, et al.
Polymorphism of XRCC1, XRCC3, and XPD genes and risk of chronic myeloid leukemia.
Biomed Res Int. 2014; 2014:213790 [PubMed] Free Access to Full Article Related Publications
The genetic polymorphisms of X-ray repair cross complementing group 1 (XRCC1), X-ray repair cross complementing group 3 (XRCC3), and xeroderma pigmentosum complementation group D (XPD) repair genes may lead to genetic instability and leukemogenesis. The purpose of the study was to evaluate the association between XRCC1 Arg399Gln, Arg280His and Arg194Trp, XRCC3 Thr241Met, and XPD Lys751Gln polymorphisms and the risk of developing CML in Romanian patients. A total of 156 patients diagnosed with CML and 180 healthy controls were included in this study. We found no association between CML and XRCC1 or XRCC3 variant genotypes in any of the investigated cases. A significant difference was observed in the variant genotype frequencies of the XPD Lys751Gln polymorphism between the patients with CML and control group (for variant homozygous genotypes, OR = 2.37; 95% CI = 1.20-4.67; P value = 0.016 and for combined heterozygous and variant homozygous genotypes, OR = 1.72; 95% CI = 1.10-2.69; P value = 0.019). This was also observed when analyzing the variant 751Gln allele (OR = 1.54; 95% CI = 1.13-2.11; P value = 0.008). Our results suggest that the XPD Lys751Gln variant genotype increases the risk of CML.

Wu JS, Chen YP, Wang LC, et al.
Implication of polymorphisms in DNA repair genes with an increased risk of hepatocellular carcinoma.
Genet Mol Res. 2014; 13(2):3812-8 [PubMed] Related Publications
We explored the association between 4 XRCC1 (Arg194Trp and Arg399Gln) and XPD (Asp312Asn and Lys751Gln) polymorphisms with the development and prognosis of hepatocellular carcinoma (HCC). A total of 218 cases with HCC and 277 healthy controls were included in the study. Genotyping of the XRCC1 (Arg194Trp and Arg399Gln) and XPD (Asp312Asn and Lys751Gln) polymorphisms was performed in a 384-well plate format on the Sequenom MassARRAY platform. We found that individuals with the XRCC1 399AA genotype had a higher risk of HCC compared with the GG genotype (odds ratio, OR = 1.85, 95% confidence interval, CI = 1.03-3.23). Similarly, individuals carrying the XPD 751GG genotype showed a greatly increased risk of HCC (OR = 2.97, 95%CI = 126- 7.38). Cox regression analysis showed that individuals carrying XPD 751Gln/Gln genotypes had a 0.30-fold increased risk of death from HCC. These results suggest that polymorphisms in XRCC1 and XPD may have functional significance in HCC.

Mirecka A, Paszkowska-Szczur K, Scott RJ, et al.
Common variants of xeroderma pigmentosum genes and prostate cancer risk.
Gene. 2014; 546(2):156-61 [PubMed] Related Publications
The genetic basis of prostate cancer (PC) is complex and appears to involve multiple susceptibility genes. A number of studies have evaluated a possible correlation between several NER gene polymorphisms and PC risk, but most of them evaluated only single SNPs among XP genes and the results remain inconsistent. Out of 94 SNPs located in seven XP genes (XPA-XPG) a total of 15 SNPs were assayed in 720 unselected patients with PC and compared to 1121 healthy adults. An increased risk of disease was associated with the XPD SNP, rs1799793 (Asp312Asn) AG genotype (OR=2.60; p<0.001) and with the AA genotype (OR=531; p<0.0001) compared to the control population. Haplotype analysis of XPD revealed one protective haplotype and four associated with an increased disease risk, which showed that the A allele (XPD rs1799793) appeared to drive the main effect on promoting prostate cancer risk. Polymorphism in XPD gene appears to be associated with the risk of prostate cancer.

Zhou M, Ding YJ, Feng Y, et al.
Association of xeroderma pigmentosum group D (Asp312Asn, Lys751Gln) and cytidine deaminase (Lys27Gln, Ala70Thr) polymorphisms with outcome in Chinese non-small cell lung cancer patients treated with cisplatin-gemcitabine.
Genet Mol Res. 2014; 13(2):3310-8 [PubMed] Related Publications
Xeroderma pigmentosum group D (XPD) plays a key role in the repair of DNA and platinum resistance lesions. Cytidine deaminase (CDA) genes determine the velocity of gemcitabine catalysis. This study aimed to investigate the relationship between XPD and CDA genotypes and outcome in non-small lung cancer (NSCLC) patients. We used polymerase chain reaction-restriction fragment length polymorphism to evaluate genetic polymorphisms of XPD (Asp312Asn and Lys751Gln) and CDA (Lys27Gln and Ala70Thr) in 93 NSCLC patients treated with a cisplatin-gemcitabine regimen. There were no significant correlations between the XPD polymorphisms Asp312Asn and Lys751Gln with clinical benefits (P>0.05). Time to progression (TTP) did not differ between patients with wild type genotypes and those heterozygous for the single nucleotide polymorphism loci of XPD. However, a significant difference was observed in overall survival (OS) between XPD Asp312Asp and XPD Asp312Asn individuals (20.0 vs 12.4 months, P=0.04). Furthermore, the OS of patients with wild type genotypes was longer (20.5 months) than that of patients carrying the XPD 751Lys/Gln polymorphism (11.5 months). No significant differences in TTP or OS were observed in patients carrying different genotypes of CDA Lys27Gln, and no mutations were observed at the CDA Ala70Thr site. These results provide suggestive evidence of a favorable effect for the XPD 312Asp/Asp and XPD 751Lys/Lys genotypes with respect to overall survival rates in platinum-treated NSCLC patients. However, the CDA 27 polymorphism does not appear to affect the efficacy of gemcitabine.

Du H, Guo N, Shi B, et al.
The effect of XPD polymorphisms on digestive tract cancers risk: a meta-analysis.
PLoS One. 2014; 9(5):e96301 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The Xeroderma pigmento-sum group D gene (XPD) plays a key role in nucleotide excision repair. Single nucleotide polymorphisms (SNP) located in its functional region may alter DNA repair capacity phenotype and cancer risk. Many studies have demonstrated that XPD polymorphisms are significantly associated with digestive tract cancers risk, but the results are inconsistent. We conducted a comprehensive meta-analysis to assess the association between XPD Lys751Gln polymorphism and digestive tract cancers risk. The digestive tract cancers that our study referred to, includes oral cancer, esophageal cancer, gastric cancer and colorectal cancer.
METHODS: We searched PubMed and EmBase up to December 31, 2012 to identify eligible studies. A total of 37 case-control studies including 9027 cases and 16072 controls were involved in this meta-analysis. Statistical analyses were performed with Stata software (version 11.0, USA). Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association.
RESULTS: The results showed that XPD Lys751Gln polymorphism was associated with the increased risk of digestive tract cancers (homozygote comparison (GlnGln vs. LysLys): OR = 1.12, 95% CI = 1.01-1.24, P = 0.029, P heterogeneity = 0.133). We found no statistical evidence for a significantly increased digestive tract cancers risk in the other genetic models. In the subgroup analysis, we also found the homozygote comparison increased the susceptibility of Asian population (OR = 1.28, 95% CI = 1.01-1.63, P = 0.045, P heterogeneity = 0.287). Stratified by cancer type and source of control, no significantly increased cancer risk was found in these subgroups. Additionally, risk estimates from hospital-based studies and esophageal studies were heterogeneous.
CONCLUSIONS: Our meta-analysis suggested that the XPD 751Gln/Gln genotype was a low-penetrate risk factor for developing digestive tract cancers, especially in Asian populations.

Hui L, Yue S, Gao G, et al.
Association of single-nucleotide polymorphisms in ERCC1 and ERCC2 with glioma risk.
Tumour Biol. 2014; 35(8):7451-7 [PubMed] Related Publications
We conducted a case-control study to assess the role of three single-nucleotide polymorphisms (SNPs) in excision repair cross-complementation group 1 (ERCC1) and two SNPs in excision repair cross-complementation group 2 (ERCC2) on the glioma risk in a Chinese population, and investigate the gene-environmental interaction for the cancer risk. A 1:2 matched case-control study was conducted. Logistic regression analysis revealed that individuals carrying ERCC1 rs2298881 CC genotype were associated with risk of glioma when compared with AA genotype carriers. The significant associations of ERCC1 rs2298881 polymorphism with glioma susceptibility were observed in both the dominant and the recessive models. In a stratification analysis, we found that ERCC1 rs2298881 variants showed an increased association with the risk of glioma in males, ever smokers, and high-grade glioma cases. In conclusion, our study suggests that ERCC1 rs2298881 polymorphism is associated with risk of glioma in codominant, dominant, and recessive models, especially in males, smokers, and high-grade glioma cases. This finding could be useful in revealing the genetic characteristics of glioma and suggests more effective strategies for prevention and treatment.

Visuvanathan S, Chong PP, Yap YY, et al.
Distribution and haplotype associations of XPD Lys751Gln, XRCC1 Arg280His and XRCC1 Arg399Gln polymorphisms with nasopharyngeal carcinoma in the Malaysian population.
Asian Pac J Cancer Prev. 2014; 15(6):2747-51 [PubMed] Related Publications
BACKGROUND: DNA repair pathways play a crucial role in maintaining the human genome. Previous studies associated DNA repair gene polymorphisms (XPD Lys751Gln, XRCC1 Arg280His and XRCC1 Arg399Gln) with nasopharyngeal carcinoma. These non-synonymous polymorphisms may alter DNA repair capacity and thus increase or decrease susceptibility. The present study aimed to determine the genotype distribution of XPD codon 751, XRCC1 codon 280 and codon 399 polymorphisms and haplotype associations among NPC cases and controls in the Malaysian population.
MATERIALS AND METHODS: We selected 157 NPC cases and 136 controls from two hospitals in Kuala Lumpur, Malaysia for this study. The polymorphisms studied were genotyped by PCR-RFLP assay and allele and genotype frequencies, haplotype and linkage disequilibrium were determined using SNPstat software.
RESULTS: For the XPD Lys751Gln polymorphism, the frequency of the Lys allele was higher in cases than in controls (94.5% versus 85.0%). For the XRCC1 Arg280His polymorphism, the frequency of Arg allele was 90.0% and 89.0% in cases and controls, respectively and for XRCC1 Arg399Gln the frequency of the Arg allele was 72.0% and 72.8% in cases and controls respectively. All three polymorphisms were in linkage disequilibrium. The odds ratio from haplotype analysis for these three polymorphisms and their association with NPC was 1.93 (95%CI: 0.90-4.16) for haplotype CGC vs AGC allele combinations. The global haplotype association with NPC gave a p-value of 0.054.
CONCLUSIONS: Our study provides an estimate of allele and genotype frequencies of XRCC1Arg280His, XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms in the Malaysian population and showed no association with nasopharyngeal cancer.

Saikia BJ, Phukan RK, Sharma SK, et al.
Interaction of XRCC1 and XPD gene polymorphisms with lifestyle and environmental factors regarding susceptibility to lung cancer in a high incidence population in North East India.
Asian Pac J Cancer Prev. 2014; 15(5):1993-9 [PubMed] Related Publications
BACKGROUND: This study aimed to explore the role of XRCC1 (Arg399Gln) and XPD (Lys751Gln) gene polymorphisms, lifestyle and environmental factors as well as their possible interactions in propensity to develop lung cancer in a population with high incidence from North East India.
MATERIALS AND METHODS: A total of 272 lung cancer cases and 544 controls were collected and XRCC1 (Arg399Gln) and XPD (Lys751Gln) genotypes were analyzed using a polymerase chain reaction based restriction fragment length polymorphism assay. Conditional multiple logistic regression analysis was used to calculate adjusted odds ratios and 95% confidence intervals after adjusting for confounding factors.
RESULTS: The combined Gln/Gln genotype of XRCC1 and XPD genes (OR=2.78, CI=1.05-7.38; p=0.040) was significantly associated with increased risk for lung cancer. Interaction of XRCC1Gln/Gln genotype with exposure of wood combustion (OR=2.56, CI=1.16-5.66; p=0.020), exposure of cooking oil fumes (OR=3.45, CI=1.39-8.58; p=0.008) and tobacco smoking (OR=2.54, CI=1.21-5.32; p=0.014) and interaction of XPD with betel quid chewing (OR=2.31, CI=1.23-4.32; p=0.009) and tobacco smoking (OR=2.13, CI=1.12-4.05; p=0.022) were found to be significantly associated with increased risk for lung cancer.
CONCLUSIONS: Gln/Gln alleles of both XRCC1 and XPD genes appear to amplify the effects of household exposure, smoking and betel quid chewing on lung cancer risk in the study population.

Tengström M, Mannermaa A, Kosma VM, et al.
MnSOD rs4880 and XPD rs13181 polymorphisms predict the survival of breast cancer patients treated with adjuvant tamoxifen.
Acta Oncol. 2014; 53(6):769-75 [PubMed] Related Publications
UNLABELLED: The enzyme manganese superoxide dismutase (MnSOD) defends against oxidative stress caused by reactive oxygen species (ROS), whereas Xeroderma pigmentosum group D (XPD) protein is involved in DNA repair. Polymorphisms in these genes have previously been associated with the outcome of breast cancer.
MATERIAL AND METHODS: Two gene polymorphisms, the MnSOD Val16Ala (rs4880A>G) and the XPD Lys751Gln (rs13181A>C), were analyzed in a cohort of 396 Finnish breast cancer patients by using PCR-RFLP-based methods in a prospective case-control study. The overall survival (OS), breast cancer-specific survival (BCSS), and relapse-free survival (RFS), assessed by using Kaplan-Meier survival analysis and multivariate Cox regression analysis, were evaluated according to the adjuvant treatments and the rs4880 and rs13181 genotypes.
RESULTS: In the combined analysis of rs4880 and rs13181 genotypes for patients treated with adjuvant tamoxifen (TAM) an increasing number of low-risk genotypes (rs4880 AA, rs4880 AG, or rs13181 AA) was significantly associated with better RFS, BCSS, and OS (n=64). In addition, there was improved BCSS and RFS among TAM-treated patients carrying the wild-type rs4880 A allele as compared with the other genotypes (n=64). The wild-type rs13181 AA genotype was similarly associated with better RFS and BCSS in the TAM-treated population (n=65).
CONCLUSION: This is the first study to show that the MnSOD rs4880 and XPD rs13181 polymorphisms may influence the outcome of breast cancer patients receiving adjuvant TAM monotherapy. Patients carrying the rs4880 A allele or rs13181 AA genotype may have a reduced ability to scavenge ROS and repair the DNA damage generated by TAM treatment.

Chabot PR, Raiola L, Lussier-Price M, et al.
Structural and functional characterization of a complex between the acidic transactivation domain of EBNA2 and the Tfb1/p62 subunit of TFIIH.
PLoS Pathog. 2014; 10(3):e1004042 [PubMed] Free Access to Full Article Related Publications
Infection with the Epstein-Barr virus (EBV) can lead to a number of human diseases including Hodgkin's and Burkitt's lymphomas. The development of these EBV-linked diseases is associated with the presence of nine viral latent proteins, including the nuclear antigen 2 (EBNA2). The EBNA2 protein plays a crucial role in EBV infection through its ability to activate transcription of both host and viral genes. As part of this function, EBNA2 associates with several host transcriptional regulatory proteins, including the Tfb1/p62 (yeast/human) subunit of the general transcription factor IIH (TFIIH) and the histone acetyltransferase CBP(CREB-binding protein)/p300, through interactions with its C-terminal transactivation domain (TAD). In this manuscript, we examine the interaction of the acidic TAD of EBNA2 (residues 431-487) with the Tfb1/p62 subunit of TFIIH and CBP/p300 using nuclear magnetic resonance (NMR) spectroscopy, isothermal titration calorimeter (ITC) and transactivation studies in yeast. NMR studies show that the TAD of EBNA2 binds to the pleckstrin homology (PH) domain of Tfb1 (Tfb1PH) and that residues 448-471 (EBNA2₄₄₈₋₄₇₁) are necessary and sufficient for this interaction. NMR structural characterization of a Tfb1PH-EBNA2₄₄₈₋₄₇₁ complex demonstrates that the intrinsically disordered TAD of EBNA2 forms a 9-residue α-helix in complex with Tfb1PH. Within this helix, three hydrophobic amino acids (Trp458, Ile461 and Phe462) make a series of important interactions with Tfb1PH and their importance is validated in ITC and transactivation studies using mutants of EBNA2. In addition, NMR studies indicate that the same region of EBNA2 is also required for binding to the KIX domain of CBP/p300. This study provides an atomic level description of interactions involving the TAD of EBNA2 with target host proteins. In addition, comparison of the Tfb1PH-EBNA2₄₄₈₋₄₇₁ complex with structures of the TAD of p53 and VP16 bound to Tfb1PH highlights the versatility of intrinsically disordered acidic TADs in recognizing common target host proteins.

Lu B, Li J, Gao Q, et al.
Laryngeal cancer risk and common single nucleotide polymorphisms in nucleotide excision repair pathway genes ERCC1, ERCC2, ERCC3, ERCC4, ERCC5 and XPA.
Gene. 2014; 542(1):64-8 [PubMed] Related Publications
Because the molecular mechanisms underlying the development of laryngeal cancer are not well understood, we conducted a case-control study to determine the association between eight common SNPs in NER pathway genes and risk of laryngeal cancer, and the association between genetic polymorphisms and environmental factors. A 1:1 matched case-control study of 176 cases and 176 controls was conducted. Laryngeal cancer cases were more likely to smoke and drink (all P values<0.05). Subjects with the ERCC1 rs11615 CC genotype and C allele had an increased risk of laryngeal cancer. Similarly, individuals with the ERCC5 rs17655 GG genotype and G allele had an increased risk of laryngeal cancer. Gene-gene interaction analysis showed that subjects carrying ERCC1 rs11615 C allele and XPG/ERCC5 rs17655 G allele had a greatly increased risk of breast cancer. Stratified analysis revealed that the interaction between polymorphisms of ERCC1 rs11615 and ERCC5 rs17655 and smoking on cancer risk was statistically significant, and ERCC1 rs11615 polymorphisms also had a significant interaction with drinking habit. In conclusion, our study suggests that ERCC1 rs11615 and ERCC5 rs17655 polymorphisms are associated with increased risk of laryngeal cancer, and that they confer more risk among smokers and drinkers.

Wu Y, Yang Y
Complex association between ERCC2 gene polymorphisms, gender, smoking and the susceptibility to bladder cancer: a meta-analysis.
Tumour Biol. 2014; 35(6):5245-57 [PubMed] Related Publications
Genetic polymorphisms in DNA repair genes may be involved in increasing the risk of bladder cancer. Association studies on the excision repair cross-complementation group 2 (ERCC2) gene polymorphisms and bladder cancer risk have reported conflicting results. The aim of this meta-analysis of eligible cancer case-control studies is to investigate the role of ERCC2 SNPs (Arg156Arg, Asp312Asn, and Lys751Gln), gender and smoking in determining susceptibility to bladder cancer. A literature search was conducted in the PubMed, Embase, Web of Science, Cochrane Library, and Google Scholar databases to indentify eligible studies published before December 1, 2013. We performed a meta-analysis of 23 case-control studies with a total of 7,062 bladder cancer patients and 8,832 controls. The overall analysis suggested that ERCC2 Arg156Arg, Asp312Asn, and Lys751Gln are associated with increased bladder cancer risk. For ERCC2 Arg156Arg, the mutant allele was associated with a 1.36-fold (95 % CI=1.15-1.61) increased risk of bladder cancer. For ERCC2 Asp312Asn, individuals with the Asn allele were associated with a 1.29-fold (95 % CI=1.13-1.48) increased risk of bladder cancer. For ERCC2 Lys751Gln, individuals who carried the variant heterozygote Lys/Gln or homozygote Gln/Gln had a significantly increased bladder cancer risk, compared with the wild genotype Lys/Lys (OR=1.10, 95 % CI=1.03-1.18). Furthermore, gender and smoking may modify the association between these SNPs and bladder cancer risk. This study provides the strongest evidence to date for the role of common variants of the ERCC2 gene in bladder carcinogenesis. Further studies comprehensively characterizing other DNA repair pathways and accounting for exposure to relevant environmental factors should offer further insight into the role of DNA repair in bladder cancer.

Liu D, Wu D, Li H, Dong M
The effect of XPD/ERCC2 Lys751Gln polymorphism on acute leukemia risk: a systematic review and meta-analysis.
Gene. 2014; 538(2):209-16 [PubMed] Related Publications
AIMS: Epidemiological studies have assessed the association between xeroderma pigmentosum group D (XPD) Lys751Gln and acute leukemia risk with conflicting results. We performed this meta-analysis to derive a more precise estimation of the relationship. Pooled odds ratio (OR) with 95% confidence interval (95% CI) was used to assess the strength of the association.
RESULTS: Ten published case-control studies including a total of 1494 cases and 2259 controls were identified. Overall, significant risk effects of Lys751Gln genotype was found under the dominant model (OR=1.16; 95% CI=1.01-1.34; P=0.032). When stratified by clinical types, the variant genotype was associated with the acute myeloid leukemia (AML) risk under the heterozygote comparison (OR=1.20; 95% CI=1.00-1.43; P=0.048), the homozygote comparison (OR=1.35; 95% CI=1.05-1.74; P=0.019) and the dominant model (OR=1.23; 95% CI=1.04-1.45; P=0.015), respectively. Furthermore, significantly increased risks were also pronounced in Caucasian AML patients (the homozygote comparison: OR=1.38; 95% CI=1.07-1.78; P=0.013; the dominant model: OR=1.23; 95% CI=1.03-1.46; P=0.020; and the recessive model: OR=1.26; 95% CI=1.00-1.60; P=0.050). No evident heterogeneities were observed for the overall data under all genetic models. In addition, no statistical evidence for publication bias was found using the method of Begg's and Egger's tests.
CONCLUSION: This meta-analysis suggested that XPD Lys751Gln polymorphism might be a risk factor for AML and Caucasian acute leukemia patients.

Zhang L, Ma W, Li Y, et al.
Pharmacogenetics of DNA repair gene polymorphisms in non-small-cell lung carcinoma patients on platinum-based chemotherapy.
Genet Mol Res. 2014; 13(1):228-36 [PubMed] Related Publications
Individual differences in chemosensitivity and clinical outcome of non-small-cell lung carcinoma (NSCLC) patients can be influenced by host-inherited factors. We investigated the impact of XRCC1 Arg194Trp, XRCC1 Arg280His, XRCC1 Arg399Gln, XPD Arg156Arg, XPD Asp312Asn, XPD Asp711Asp, and XPD Lys751Gln gene polymorphisms on treatment efficacy in 375 NSCLC patients on platinum-based chemotherapy. We also examined progression-free survival and overall survival. The gene polymorphisms were analyzed by duplex PCR. The patients with XRCC1 399A/A had a significantly better response to chemotherapy. Individuals with XPD 711 Asp and XPD 312 Asn alleles responded poorly to chemotherapy when compared with the wide-type genotype. The adjusted hazard ratio (HR) in the Cox regression model was calculated. The XRCC1 399A/A polymorphism was associated with better progression free survival and overall survival of NSCLC patients (HR=0.61 and 0.55). On the other hand, the XPD 711 Asp allele was associated with poorer progression free survival and overall survival compared to the C/C genotype, with HRs of 1.89 and 1.90. The XPD 312 Asn allele was found to be associated with non-significantly reduced survival of NSCLC patients (HR = 1.73). In conclusion, we found the polymorphisms of XRCC1 and XPD to be related to the efficacy of platinum-based chemotherapy in NSCLC patients. This information should aid in therapeutic decisions for individualized therapy in NSCLC cases.

Lin H, Lin D, Zheng C
Association of XPD Lys751Gln polymorphism with head and neck cancer susceptibility: evidence from 11,443 subjects.
Diagn Pathol. 2014; 9:15 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Whether the single nucleotide polymorphism (SNP) Lys751Gln of xeroderma pigmentosum group D(XPD) gene increases susceptibility to head and neck cancer (HNC) is controversial and undetermined. Therefore, we conducted this meta-analysis to systematically assess the possible association between them.
METHODS: The OVID, Medline, Embase, Pubmed, Web of Science databases were searched to identify the eligible studies. The odds ratio (OR) with 95% confidence interval (95% CI) were used to assess the strength of association.
RESULTS: A total of 11,443 subjects from eighteen studies were subjected to meta-analysis. Overall, XPD Lys751Gln polymorphism had no association with increased HNC risk under all five genetic models (P > 0.05). In the subgroup analysis by ethnicity and source of controls, still no significant association was found under five genetic models (P > 0.05). In the subgroup analysis by cancer type, XPD Lys751Gln polymorphism had statistically significant association with elevated laryngeal cancer (LC) and nasopharyngeal cancer (NPC) risk under heterozygous comparison and dominant model (P<0.05) and borderline significantly increased risk was found under allele contrast for LC and NPC. Carriers of Lys allele and Lys/Lys genotype may be associated with elevated LC and NPC risk.
CONCLUSIONS: There is overall lack of association between XPD Lys751Gln polymorphism and HNC risk under all five genetic models and still no significant association was found in the subgroup analysis by ethnicity and source of controls. However, XPD Lys751Gln polymorphism was significantly associated with susceptibility to LC and NPC and the Lys allele and Lys/Lys genotype of XPD Lys751Gln polymorphism may be a risk factor for LC and NPC. However, relatively modest sample sizes were included in this meta-analysis and studies with large sample sizes and representative population are warranted to further clarify this finding.
VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5628716106316015.

Smolarz B, Makowska M, Samulak D, et al.
Single nucleotide polymorphisms (SNPs) of ERCC2, hOGG1, and XRCC1 DNA repair genes and the risk of triple-negative breast cancer in Polish women.
Tumour Biol. 2014; 35(4):3495-502 [PubMed] Free Access to Full Article Related Publications
Triple-negative breast cancer (TNBC) refers to about 15-20% of all breast cancer cases. It is characterized by worse clinical outcome, poor prognosis, and absence of prognostic indicators. Several polymorphisms in the nucleotide excision repair (NER) and base excision repair (BER) gene have been extensively studied in association with various human cancers. The aim of this study was to evaluate the role of the hOGG1-Ser326Cys (rs13181), XRCC1-Arg194Trp (rs1799782), and ERCC2-Lys751Gln (rs13181) gene polymorphisms with clinical parameters and the risk for development of triple-negative breast cancer. Our research included 70 patients with TNBC and 70 healthy controls. Gene polymorphisms were genotyped by the PCR-RFLP (restriction fragment length polymorphism) method. The genotype distributions were contrasted by the chi-square test, and the significance of the polymorphism was assessed by multiple logistic regression producing odds ratios (ORs) and 95% confidence intervals (CIs). In the present work, a relationship was identified between ERCC2-Lys751Gln polymorphism and the incidence of triple-negative breast cancer. An association was observed between triple-negative breast carcinoma occurrence and the presence of Gln/Gln genotype (OR = 5.71 (2.12-5.43), p = 0.0007). A tendency for an increased risk of TNBC was detected with the occurrence of 751Gln allele of ERCC2 polymorphism. No significant associations between Ser326Cys and Arg194Trp genotype and TNBC were observed. We suggest that the Lys751Gln polymorphism of the ERCC2 gene may be risk factors for triple-negative breast cancer development in Polish women.

Zhang Y, Wang L, Wang P, et al.
Association of single nucleotide polymorphisms in ERCC2 gene and their haplotypes with esophageal squamous cell carcinoma.
Tumour Biol. 2014; 35(5):4225-31 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC), one of the leading causes of cancer death worldwide, occurs at a relatively high frequency in China. To investigate whether common excision repair cross-complementing rodent repair group 2 (ERCC2) variants (rs3916874 G>C, rs238415 C>G, rs1618536 G>A, rs1799793 G>A, and rsl3181 A>C) were associated with ESCC risk, a case-control study was conducted, including 405 cases with ESCC and 405 age and sex 1:1 matched cancer-free controls. The result showed that rsl3181 AC/CC genotypes was associated with an increased risk of ESCC (OR: 1.45, 95% CI: 1.05-2.00), and two ERCC2 haplotypes Grs3916874Crs238415Grs1618536Grs1799793Crsl3181 (Hap5) and Grs3916874Grs238415Ars1618536Grs1799793Crsl3181 (Hap7) were associated with increased risk of ESCC (OR: 2.16, 95 % CI: 1.27-3.57 for Hap5 and OR: 3.72; 95 % CI: 1.89-6.63 for Hap7, respectively), while Grs3916874Grs238415Grs1618536Grs1799793Arsl3181 (Hap4) was associated with decreased risk of ESCC (OR: 0.47, 95% CI: 0.35-0.71). Gene-environment interaction analysis by multifactor dimensionality reduction (MDR) software showed that there was an interaction among rs238415, rs1618536, and family history of cancer with a P value under 0.0001 (OR: 3.23: 95% CI: 2.37-4.40). These results suggested that genetic variations in the ERCC2 gene were associated with risk of ESCC, and there was a significant interaction between gene polymorphisms and family history of cancer in the etiology of ESCC.

Li W, Li K, Zhao L, Zou H
DNA repair pathway genes and lung cancer susceptibility: a meta-analysis.
Gene. 2014; 538(2):361-5 [PubMed] Related Publications
OBJECTIVE: DNA repair pathway genes have been implicated to play an important role in the development of lung cancer. However, contradictory results are often reported by various studies, making it difficult to interpret them. So in this meta-analysis, we have assessed the association between lung cancer risk and two DNA repair pathway genes. XRCC1 and ERCC2, by analyzing 67 published case-control studies.
RESEARCH DESIGN AND METHODS: We searched PubMed, Embase and Web of Science using terms "XRCC1" or "XPD" or "ERCC2" and "lung cancer" on August 1, 2012. Three criteria were applied to select included studies for resulting studies. Information was carefully extracted by two investigators independently. We used pooled odds ratio (OR) to assess the effect of a polymorphism, and a dominant model was applied where genotypes that contain the non-reference allele were combined together. All the calculations were performed using STATA version 11.0.
MAIN OUTCOME MEASURES AND RESULTS: Three common nonsynonymous polymorphisms in XRCC1, codon 194, codon 280 and codon 399, and two common nonsynonymous polymorphisms in ERCC2, codon 312 and codon 751, were analyzed. The result showed in total population, Lys751Gln in ERCC2 is associated with an increase of lung cancer risk, with a summary OR as 1.15. No association was found for any other polymorphisms. When studies were stratified by ethnicity, the risk effect of Lys751Gln in ERCC2 was found only in Caucasians, not in Asians.
CONCLUSIONS: In conclusion, Lys751Gln in ERCC2 is associated with lung cancer, and the risk effect probably exists in Caucasians. By contrast, polymorphisms in XRCC1 are less likely to be susceptible to lung cancer risks.

Mandal RK, Yadav SS, Panda AK
Meta-analysis on the association of nucleotide excision repair gene XPD A751C variant and cancer susceptibility among Indian population.
Mol Biol Rep. 2014; 41(2):713-9 [PubMed] Related Publications
Polymorphism A751C (A>C) in XPD gene has shown susceptibility to many cancers in Indian population; however the results of these studies are inconclusive. Thus, we performed this meta-analysis to estimate the association between XPD A751C polymorphism and overall cancer susceptibility. We quantitavely synthesized all published studies of the association between XPD A751C polymorphism and cancer risk. Pooled odds ratios (ORs) and 95 % CI were estimated for allele contrast, homozygous, heterozygous, dominant and recessive genetic model. A total of thirteen studies including 3,599 controls and 3,087 cancer cases were identified and analyzed. Overall significant results were observed for C allele carrier (C vs. A: p = 0.001; OR 1.372, 95 % CI 1.172-1.605) variant homozygous (CC vs. AA: p = 0.001; OR 1.691, 95 % CI 1.280-2.233) and heterozygous (AC vs. AA: p = 0.001; OR 1.453, 95 % CI 1.215-1.737) genotypes. Similarly dominant (CC+AC vs. AA: p = 0.001; OR 1.512, 95 % CI 1.244-1.839) and recessive (CC vs. AA+AC: p = 0.001; OR 1.429, 95 % CI 1.151-1.774) genetic models also demonstrated risk of developing cancer. This meta-analysis suggested that XPD A751C polymorphism likely contribute to cancer susceptibility in Indian population. Further studies about gene-gene and gene-environment interactions are required.

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