XPA A23G, XPC Lys939Gln, XPD Lys751Gln and XPD Asp312Asn polymorphisms, interactions with smoking, alcohol and dietary factors, and risk of colorectal cancer

Polymorphisms in the XPD and the XPC gene have been associated with a lower DNA repair capacity. We determined the risk of colorectal cancer in association with the four polymorphisms XPA A23G, XPC Lys939Gln, XPD Lys751Gln and XPD Asp312Asn, and interactions between the polymorphisms and the environmental factors: smoking intensity, intake of alcohol, red meat, processed meat, fish and poultry, fruits and vegetables and dietary fibres, in relation to development of colorectal cancer in a study population of 405 colorectal cancer cases and a comparison group of 810 persons, nested within the Danish prospective cohort, Diet, Cancer and Health, of 57053 cohort members. No association was found between the XPC Lys939Gln, XPA A23G, XPD Lys751Gln, and XPD Asp312Asn polymorphisms and risk of colorectal cancer. The association of the XPD Lys751Gln polymorphism was statistically significantly different between genders, with a lower risk of colorectal cancer among women carrying the variant allele. We observed a statistically significant interaction between the XPC Lys939Gln polymorphism and consumption of red meat, with a 3.7-fold increase in colorectal cancer risk per 100g red meat intake per day among carriers of the homozygous variant, but virtually no effect of red meat intake among carriers of the wild type allele. In the light of the multiple comparisons being made, this result may be a chance finding. The results showed no interaction between the XPD Lys751Gln, XPA A23G, and XPD Asp312Asn polymorphisms and the environmental factors for the development of colorectal cancer. Overall, the results of the present study indicate that the four polymorphisms are not of major importance in colorectal cancer carcinogenesis.     

The Effect of XPD/ERCC2 Polymorphisms on Gastric Cancer Risk among Different Ethnicities: A Systematic Review and Meta-Analysis

Background

Potential xeroderma pigmentosum group D (XPD), also called excision repair cross-complimentary group two (ERCC2), Lys751Gln and Asp312Asn polymorphisms have been implicated in gastric cancer risk among different ethnicities.

Methods

We aimed to explore the effect of XPD Lys751Gln and Asp312Asn polymorphisms on the susceptibility to gastric cancer among different ethnicities through a systematic review and meta-analysis. Each initially included article was scored for quality appraisal. Desirable data were extracted and registered into databases. 13 studies were ultimately eligible for the meta-analysis of Lys751Gln polymorphism and 9 studies for the meta-analysis of Asp312Asn polymorphism. We adopted the most probably appropriate genetic model (recessive model) for both Lys751Gln and Asp312Asn polymorphisms. Potential sources of heterogeneity were sought out via subgroup and sensitivity analyses, and publication biases were estimated.

Results

Statistically significant findings were apparently noted in Asians but not in Caucasians for both XPD Lys751Gln and XPD Asp312Asn polymorphisms. A statistically significant finding could be seen in noncardia-type gastric cancer for XPD Lys751Gln polymorphism. A statistically significant finding could also be seen in high quality subgroup, small-and-moderate sample size subgroup, articles published after 2007, or PCR-RFLP genotyping subgroup for XPD Asp312Asn polymorphism.

Conclusions

Our meta-analysis indicates that XPD Gln751Gln (CC) genotype and Asn312Asn (AA) genotype may seem to be more susceptible to gastric cancer in Asian populations but not in Caucasian populations, suggesting that the two genotypes may be important biomarkers of gastric cancer susceptibility for Asian populations, the assumption that needs to be further confirmed in well-designed studies among different ethnicities. Gln751Gln (CC) genotype may also be associated with noncardia-type gastric cancer risk, which should also be confirmed among different ethnicities in the future.     

Two regions in chromosome 19q13.2-3 are associated with risk of lung cancer

Lung cancer is the most common fatal cancer among Danish men, and the incidence rate is increasing among women. In a case-cohort study, we have investigated the occurrence of lung cancer in relation to a high-risk haplotype, previously identified for breast cancer among post-menopausal women, and in relation to the closely linked polymorphisms XPD Asp312Asn and Lys751Gln. Among 54220 members of a Danish prospective cohort study aged 50-64 at entry, 265 lung cancer cases were identified and a sub-cohort comprising 272 individuals was used for comparison. Among women in the 50-55 year age interval, homozygous carriers of the high-risk haplotype were at increased risk of lung cancer (RR=7.02, 95% CI=1.88-26.18). In the 56-60 year and 61-70 year age intervals, no associations were observed. Among men, no statistically significant associations were found in any age interval. Female homozygous carriers of the variant allele of XPD Lys751Gln were at significantly increased risk of lung cancer in the two younger age-intervals (50-55 years: RR=5.60, 95% CI=1.18-26.45, 56-60 years: RR=10.60, 95% CI=1.50-75.64). Among men, carriers of the variant allele of XPD Lys751Gln had a non-significantly increased risk of lung cancer in the youngest age interval (RR=6.38, 95% CI=0.74-54.90). When the polymorphisms in XPD Asp312Asn and Lys751Gln were mutually adjusted, XPD Asp312Asn was not associated with increased risk of cancer. We found no interaction between genotypes and duration of smoking. In conclusion, two regions of chromosome 19q13.2-3 seem to be associated with risk of lung cancer.     

Polymorphisms in base-excision repair and nucleotide-excision repair genes in relation to lung cancer risk

Polymorphisms in DNA repair genes may be associated with differences in DNA repair capacity, thereby influencing the individual susceptibility to smoking-related cancer. We investigated the association of 10 base-excision and nucleotide-excision repair gene polymorphisms (XRCC1 -77 T/C, Arg194Trp, Arg280His and Arg399Gln; APE1 Asp148Glu; OGG1 Ser326Cys; XPA -4 G/A; XPC PAT; XPD Asp312Asn and Lys751Gln) with lung cancer risk in Caucasians. Genotypes were determined by PCR-RFLP and PCR-single base extension assays in 110 lung cancer patients and 110 age- and sex-matched controls, and the results were analyzed using logistic regression adjusted for relevant covariates. A significant association between the APE1 Asp148Glu polymorphism and lung cancer risk was found, with adjusted odds ratios (OR) of 3.38 (p=0.001) for the Asp/Glu genotype and 2.39 (p=0.038) for the Glu/Glu genotype. Gene-smoking interaction analyses revealed a statistically significant interaction between cumulative cigarette smoking and the XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms: these polymorphisms were significantly associated with lung cancer in nonsmokers and light smokers (<25 PY; OR=4.92, p=0.021 for XRCC1 399 Gln/Gln; OR=3.62, p=0.049 for XPD 751 Gln/Gln), but not in heavy smokers (> or =25 PY; OR=0.68, p=0.566 for XRCC1 399 Gln/Gln; OR=0.46, p=0.295 for XPD 751 Gln/Gln). Both the XRCC1 Arg194Trp and Arg280His as well as the OGG1 Ser326Cys heterozygous genotypes were associated with a significantly reduced risk for lung cancer (OR=0.32, p=0.024; OR=0.25, p=0.028; OR=0.51, p=0.033, respectively). No associations with lung cancer risk were found for the XRCC1 -77 T/C, the XPA -4 G/A and the XPC PAT polymorphisms. In conclusion, the APE1 Asp148Glu polymorphism is highly predictive for lung cancer, and cumulative cigarette smoking modifies the associations between the XRCC1 Arg399Gln and the XPD Lys751Gln polymorphisms and lung cancer risk.     

Genetic polymorphisms of xeroderma pigmentosum group D gene Asp312Asn and Lys751Gln and susceptibility to prostate cancer: A systematic review and meta-analysis

Many studies have reported the role of xeroderma pigmentosum group D (XPD) with prostate cancer risk, but the results remained controversial. To derive a more precise estimation of the relationship, a meta-analysis was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between XPD Asp312Asn and Lys751Gln polymorphisms and prostate cancer risk. A total of 8 studies including 2620 cases and 3225 controls described Asp312Asn genotypes, among which 10 articles involving 3230 cases and 3582 controls described Lys751Gln genotypes and were also involved in this meta-analysis. When all the eligible studies were pooled into this meta-analysis, a significant association between prostate cancer risk and XPD Asp312Asn polymorphism was found. For Asp312Asn polymorphism, in the stratified analysis by ethnicity and source of controls, prostate cancer risk was observed in co-dominant, dominant and recessive models, while no evidence of any associations of XPD Lys751Gln polymorphism with prostate cancer was found in the overall or subgroup analyses. Our meta-analysis supports that the XPD Asp312Asn polymorphism contributed to the risk of prostate cancer from currently available evidence. However, a study with a larger sample size is needed to further evaluate gene–environment interaction on XPD Asp312Asn and Lys751Gln polymorphisms and prostate cancer risk.     

Analysis of XPD genetic polymorphisms of esophageal squamous cell carcinoma in a population of Yili Prefecture, in Xinjiang, China

To evaluate the association with genetic polymorphisms in Xeroderma pigmentosum complementation group D (XPD) gene of esophageal squamous cell carcinoma (ESCC) risk in a population of Yili Prefecture, in Xinjiang, China. A hospital-based case–control study was designed with 571 samples including 213 ESCC patients and 358 controls with age, gender and ethnicity-matched subjects (Kazakh, Uygur and Han ethnic). Genotypes were determined by PCR restriction fragment length polymorphism (PCR-RLFP) and confirmed by sequence. Relative risk associated with a particular genotype was estimated by calculating odds ratios (OR) along with 95% confidence intervals (CI). Significant ESCC risk was observed for XPD Lys751Gln (rs13181) frequency of presence C allele (OR: 1.409, 95% CI: 1.005–1.976) in the three ethnics. XPD Asp312Asn (rs1799793) of Han ethnic was associated with a borderline decrease of ESCC (OR: 0.362, 95% CI: 0.145–0.906), however, it was associated with ESCC risk in Uygur ethnic (OR: 2.403, 95% CI: 1.087–5.310). The results demonstrated an association between the XPD Lys751Gln (rs13181) for frequency of presence C allele and risk for ESCC in the three ethnics of Yili Prefecture, in Xinjiang, China. XPD Asp312Asn (rs1799793), which was associated with a borderline decrease of Han ethnic and risk of Uygur ethnic of ESCC, may play a different role in the three ethnics of ESCC.     

Predictive Value of XPD Polymorphisms on Platinum-Based Chemotherapy in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

Background

The correlation between xeroderma pigmentosum group D (XPD) polymorphisms (Lys751Gln and Asp312Asn) and clinical outcomes of non-small cell lung cancer (NSCLC) patients, who received platinum-based chemotherapy (Pt-chemotherapy), is still inconclusive. This meta-analysis was aimed to systematically review published evidence and ascertain the exact role of XPD polymorphisms.

Methods

Databases of MEDLINE and EMBASE were searched up to April 2013 to identify eligible studies. A rigorous quality assessment of eligible studies was conducted according the Newcastle-Ottawa Quality Assessment Scales. The relationship between XPD polymorphisms and response to Pt-chemotherapy and survival was analyzed.

Results

A total of 22 eligible studies were included and analyzed in this meta-analysis. The overall analysis suggested that the XPD Lys751Gln polymorphism was not associated with response to Pt-chemotherapy or survival. However, the XPD 312Asn allele was significantly associated with poor response to Pt-chemotherapy compared with the Asp312 allele (Asn vs. Asp: OR = 0.435, 95% CI: 0.261–0.726). Additionally, the variant genotype of XPD Asp312Asn polymorphism was associated with favorable survival in Caucasian (AspAsn vs. AspAsp: HR = 0.781, 95% CI: 0.619–0.986) but unfavorable survival in Asian (AspAsn+AsnAsn vs. AspAsp: HR = 1.550, 95% CI: 1.038–2.315).

Conclusions

These results suggest that XPD Asp312Asn polymorphism may function as a predictive biomarker on platinum-based chemotherapy in NSCLC and further studies are warranted.     

<Emphasis Type="Italic">XPD</Emphasis> Lys<Superscript>751</Superscript>Gln and Asp<Superscript>312</Superscript>Asn polymorphisms and bladder cancer risk: a meta-analysis

Studies on the polymorphisms of Xeroderma Pigmentosum Group D (XPD) have shown inconclusive trends in the risk of bladder cancer. The purpose of this study is to evaluate the role of XPD single nucleotide polymorphisms in bladder cancer susceptibility. We performed a meta-analysis on all available studies, which included 5,368 and 6,683 XPD Lys⁷⁵¹Gln cases and controls and 3,220 and 4,391 Asp³¹²Asn cases and controls, respectively. Overall, Significant risk effects of Lys⁷⁵¹Gln genotype was found under recessive model contrast [Gln/Gln vs. (Gln/Lys + Lys/Lys)] [P = 0.04, OR = 1.12; 95% CI (1.01, 1.26)], and subtle but insignificantly increased risks between Lys⁷⁵¹Gln and bladder cancer were observed under allele contrast (Gln vs. Lys) and homologous contrast (Gln/Gln vs. Lys/Lys) in all subjects. The ⁷⁵¹Gln allele had no significant effect on bladder cancer in all subgroups (Asian, Caucasian and USA). Significant risk effects of Asp³¹²Asn polymorphism on bladder susceptibility were observed in all subjects under all genetic contrasts, however, stratified analyses showed that the ³¹²Asn allele showed different risk effects in USA and Caucasian. The Gln/Gln genotype acts as a risk factor in its association with bladder cancer, and the effect of Lys⁷⁵¹Gln polymorphism on bladder susceptibility should be studied with larger, stratified population; the ³¹²Asn allele has an important role in the etiology of bladder cancer whereas the ethnic background should be carefully concerned in further studies.     

Influence of polymorphisms in DNA repair genes XPD, XRCC1 and MGMT on DNA damage induced by gamma radiation and its repair in lymphocytes in vitro

DNA single-strand breaks (SSBs) were quantified by single-cell gel electrophoresis and micronucleated and apoptotic cells were quantified by microscopic assays in peripheral blood lymphocytes after irradiation on ice with 2 Gy of 60Co gamma radiation, and their association with polymorphisms of genes that encode proteins of different DNA repair pathways and influence cancer risk (XPD codon 312Asp --> Asn and 751Lys --> Gln, XRCC1 399Arg --> Gln, and MGMT 84Leu --> Phe) was studied. In unirradiated lymphocytes, SSBs were significantly more frequent in individuals older than the median age (52 years) (P = 0.015; n = 81), and the frequency of apoptotic or micronucleated cells was higher in individuals with alleles coding for Asn at XPD 312 or Gln at 751 (P = 0.030 or 0.023 ANOVA, respectively; n = 54). The only polymorphism associated with the background SSB level was MGMT 84Phe (P = 0.04, ANOVA; n = 66). After irradiation, SSB levels and repair parameters did not differ significantly with age or smoking habit. The SSB level varied more than twofold and the repair rate and level of unrepaired SSBs more than 10-fold between individuals. The presence of variant alleles coding for Asn at XPD 312 was associated with more radiation-induced SSBs (P = 0.014) and fewer unrepaired SSBs (P = 0.008), and the phenotype (> median induced SSBs/< median unrepaired SSBs) was seen in the majority of XPD 312Asn/Asn homozygotes; the odds ratio for variant homozygotes to show this phenotype was 5.2 (95% confidence interval 1.4-19.9). The hypothesis is discussed that XPD could participate in repair of ionizing radiation-induced DNA damage. While it cannot be excluded that the effects observed are due to cosegregating polymorphisms or that the responses of lymphocytes are not typical of other cell types, the results suggest that polymorphism of DNA repair genes, particularly XPD, is one factor implicated in the variability of responses to ionizing radiation between different individuals.     

Susceptibility of XPD and RAD51 genetic variants to carcinoma of urinary bladder in North Indian population

For the present study, two polymorphisms, xeroderma pigmentosum, complementation group D (XPD) Lys751Gln and RAD51 135G/C were studied with regard to bladder cancer. For XPD Lys751Gln polymorphism, an increased risk of bladder cancer was found to be associated with the Gln variant allele (odds ratio [OR]=1.86, 95% confidence interval [CI]=1.27-2.73), on taking AA (Lys/Lys) as the referent genotype. In males, the XPD 751C (Gln) allele was found to be associated with a significantly increased risk (OR=2.33, 95% CI=1.52-3.56). The inhabitants of rural areas showed a significantly increased risk with the XPD Gln allele (OR=2.59, 95% CI=1.46-4.62) when compared with those of urban areas. In smokers (OR=5.30, 95% CI=2.42-11.68), alcohol drinkers (OR=4.33, 95% CI=2.17-8.70), and nonvegetarians (OR=2.21, 95% CI=1.26-3.87), the XPD Gln allele showed a significantly increased risk toward bladder cancer. For RAD51 135G/C polymorphism, no significant difference was observed in the allelic and genotypic frequencies. Even after stratification, no significant association could be seen. After stratifying histopathologically, the RAD51 CC genotype was associted with decreased risk in subjects having superficial stage (OR=0.51, 95% CI=0.27-0.99) and with those having G2 grade (OR=0.24, 95% CI=0.09-0.62) of bladder cancer. XPD polymorphism may be a predisposing factor, but the same cannot be said for RAD51 gene polymorphism.     

Association between DNA damage, DNA repair genes variability and clinical characteristics in breast cancer patients

The cell's susceptibility to DNA damage and its ability to repair this damage are important for cancer induction, promotion and progression. In the present work we determined the level of basal (total endogenous) and endogenous oxidative DNA damage as well as polymorphism of the DNA repair genes: RAD51 (135 G/C), XRCC3 (Thr241Met), OGG1 (Ser326Cys) and XPD (Lys751Gln) in peripheral blood lymphocytes of 41 breast cancer patients and 48 healthy individuals. DNA damage was evaluated by alkaline comet assay with DNA repair enzymes: Endo III and Fpg, preferentially recognizing oxidized DNA bases. The genotypes of the polymorphisms were determined by restriction fragment length polymorphism PCR. We observed a strong association between breast cancer occurrence and the genotypes C/C of the RAD51-135G/C polymorphism, Ser/Ser of the OGG1-Ser326Cys and Lys/Gln of the XPD-Lys751Gln, whereas the genotypes G/C of the RAD51-135G/C and Lys/Lys of the XPD-Lys751Gln exerted a protective effect against breast cancer. We also found that individuals with the G/C genotype of the RAD51-135G/C polymorphism and with the Lys/Lys genotype of the XPD-Lys751Gln polymorphism displayed a lower extent of basal and oxidative DNA damage. A strong association between higher level of oxidative DNA damage and the Lys/Gln genotype of the latter polymorphism was found. We also correlated genotypes with clinical characteristics of breast cancer patients. We observed a strong association between the G/C genotype of the RAD51-135 G/C polymorphism and the expression of the progesterone receptor and between both alleles of the OGG1-Ser326Cys polymorphism and lymph node metastasis. Our results suggest that the polymorphism of the RAD51, OGG1 and XPD genes may be linked with breast cancer by the modulation of the cellular response to oxidative stress and these polymorphisms may be considered as markers in breast cancer along with the genetic or/and environmental indicators of oxidative stress.     

Association between XPD Lys751Gln polymorphism and risk of head and neck cancer: a meta-analysis

Several studies have investigated the association between Lys751Gln polymorphism in the xeroderma pigmentosum group D (XPD) gene and risk of head and neck cancer; however, the published results are conflicting. We conducted a meta-analysis that comprised 15 published case-control studies examining the association of head and neck cancer risk with XPD Lys751Gln polymorphism in different populations, based on the data identified in Medline up to November 2010. Odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the strength of the association. Overall, significantly elevated head and neck cancer risk was associated with XPD Lys751Gln polymorphism when all studies were pooled into the meta-analysis [(Gln/Gln + Lys/Gln) vs Lys/Lys: OR = 1.12, 95%CI = 1.03-1.22, P < 0.01, heterogeneity P = 0.11]. In the subgroup analysis by ethnicity, borderline significantly increased risk was found for Europeans [(Gln/Gln + Lys/Gln) vs Lys/Lys: OR = 1.11, 95%CI = 1.00-1.23, P < 0.05]. In conclusion, our meta-analysis demonstrated that XPD Lys751Gln polymorphism could be a prediction marker for risk of head and neck cancer.     

Relationship between polymorphisms of nucleotide excision repair genes and oral cancer risk in Taiwan: evidence for modification of smoking habit

Inherited polymorphisms in DNA repair genes may be associated with differences in the repair capacity and contribute to individual's susceptibility to smoking-related cancers. Both XPA and XPD encode proteins that are part of the nucleotide excision repair (NER) pathway. In a hospital-based case-control study, we have investigated the influence of XPA A-23G and XPD Lys751Gln polymorphisms on oral cancer risk in a Taiwanese population. In total, 154 patients with oral cancer, and 105 age-matched controls recruited from the Chinese Medical Hospital in Central Taiwan were genotyped. No significant association was found between the heterozygous variant allele (AG), the homozygous variant allele (AA) at XPA A-23G, the heterozygous variant allele (AC), the homozygous variant allele (CC) at XPD Lys751Gln, and oral cancer risk. There was no significant joint effect of XPA A-23G and XPD Lys751Gln on oral cancer risk either. Since XPA and XPD are both NER genes, which are very important in removing tobacco-induced DNA adducts, further stratified analyses of both genotype and smoking habit were performed. We found a synergistic effect of variant genotypes of both XPA and XPD, and smoking status on oral cancer risk. Our results suggest that the genetic polymorphisms are modified by environmental carcinogen exposure status, and combined analyses of both genotype and personal habit record are a better access to know the development of oral cancer and useful for primary prevention and early intervention.     

Impact of Two Common Xeroderma Pigmentosum Group D (XPD) Gene Polymorphisms on Risk of Prostate Cancer

Background

DNA repair genes (eg: xeroderma pigmentosum group D, XPD) may affect the capacity of encoded DNA repair enzymes to effectively remove DNA adducts or lesions, which may result in enhanced cancer risk. The association between XPD gene polymorphisms and the susceptibility of prostate cancer (PCa) was inconsistent in previous studies.

Methodology/Principal Findings

A meta-analysis based on 9 independent case-control studies involving 3165 PCa patients and 3539 healthy controls for XPD Gln751Lys SNP (single nucleotide polymorphism) and 2555 cases and 3182 controls for Asn312Asp SNP was performed to address this association. Meanwhile, odds ratio (OR) and 95% confidence intervals (CIs) were used to evaluate this relationship. Statistical analysis was performed with STATA10.0. No significant association was found between XPD Gln751Lys SNP and PCa risk. On the other hand, in subgroup analysis based on ethnicity, associations were observed in Asian (eg. Asn vs. Asp: OR = 1.34, 95%CI = 1.16–1.55; Asn/Asn+Asn/Asp vs. Asp/Asp: OR = 1.23, 95%CI = 1.07–1.42) and African (eg. Asn vs. Asp: OR = 1.31, 95%CI = 1.01–1.70; Asn/Asn vs. Asp/Asp: OR = 1.71, 95%CI = 1.03–7.10) populations for Asn312Asp SNP. Moreover, similar associations were detected in hospital-based controls studies; the frequency of Asn/Asn genotype in early stage of PCa men was poorly higher than those in advanced stage of PCa men (OR = 1.45, 95%CI = 1.00–2.11).

Conclusion/Significance

Our investigations demonstrate that XPD Asn312Asp SNP not the Gln751Lys SNP, might poorly increase PCa risk in Asians and Africans, moreover, this SNPs may associate with the tumor stage of PCa. Further studies based on larger sample size and gene-environment interactions should be conducted to determine the role of XPD gene polymorphisms in PCa risk.     

Impact of DNA repair genes polymorphism (XPD and XRCC1) on the risk of breast cancer in Egyptian female patients

The genes involved in DNA repair system play a crucial role in the protection against mutations. It has been hypothesized that functional deficiencies in highly conserved DNA repair processes resulting from polymorphic variation may increase genetic susceptibility to breast cancer (BC). The aim of the present study was to evaluate the association of genetic polymorphisms in 2 DNA repair genes, XPD (Asp312Asn) and XRCC1 (A399G), with BC susceptibility. We further investigated the potential combined effect of these DNA repair variants on BC risk. Both XPD (xeroderma pigmentosum group D) and XRCC1 (X-ray repair cross-complementing group 1) polymorphisms were characterized in 100 BC Egyptian females and 100 healthy women who had no history of any malignancy by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method and PCR with confronting two-pair primers (PCR-CTPP), using DNA from peripheral blood in a case control study. Our results revealed that the frequencies of AA genotype of XPD codon 312 polymorphism were significantly higher in the BC patients than in the normal individuals (P ≤ 0.003), and did not observe any association between the XRCC1 Arg399Gln polymorphism and risk of developing BC. Also, no association between both XPD Asp312Asn and XRCC1 A399G polymorphisms and the clinical characteristics of disease. Finally, the combination of AA(XPD) + AG(XRCC1) were significantly associated with BC risk. Our results suggested that, XPD gene is an important candidate gene for susceptibility to BC. Also, gene–gene interaction between XPD(AA) + XRCC1(AG) polymorphism may be associated with increased risk of BC in Egyptian women.     

Polymorphisms in metabolic GSTP1 and DNA-repair XRCC1 genes with an increased risk of DNA damage in pesticide-exposed fruit growers

Pesticide exposure is associated with various neoplastic diseases and congenital malformations. Previous studies have indicated that pesticides may be metabolized by cytochrome P450 3A5 or glutathione S-transferases. DNA-repair genes, including X-ray repair cross-complementing group 1 (XRCC1) and xeroderma pigmentosum group D (XPD), may also be implicated in the process of pesticide-related carcinogenesis. Thus, we investigated whether various metabolic and DNA-repair genotypes increase the risk of DNA damage in pesticide-exposed fruit growers. Using the comet assay, the extent of DNA damage was evaluated in the peripheral blood of 135 pesticide-exposed fruit growers and 106 unexposed controls. The metabolic genotypes CYP3A5 (A(-44)G) and GSTP1 (Ile105Val) and DNA-repair genotypes XRCC1 (Arg399Gln, Arg194Trp, T(-77)C) and XPD (Asp312Asn, Lys751Gln) were identified by polymerase chain reaction. Our multiple regression model for DNA tail moment showed that age, high pesticide exposure, low pesticide exposure, GSTP1 Ile-Ile, and XRCC1 399 Arg-Arg genotype were associated with increased DNA tail moment (DNA damage). Further analysis of interaction between GSTP1 and XRCC1 genes that increase susceptibility revealed a significant difference in DNA tail moment for high pesticide-exposed subjects carrying both GSTP1 Ile-Ile with XRCC1 399 Arg-Arg genotypes (2.49+/-0.09 microm/cell; P=0.004), compared to those carrying GSTP1 Ile-Val/Val-Val with XRCC1 399 Arg-Gln/Gln-Gln genotypes (1.98+/-0.15 microm/cell). These results suggest that individuals with susceptible metabolic GSTP1 and DNA-repair XRCC1 genotypes may be at increased risk of DNA damage due to pesticide exposure.     

XPD Lys751Gln polymorphism and esophageal cancer susceptibility: a meta-analysis of case–control studies

The published data on the association between xeroderma pigmentosum group D (XPD) Lys751Gln polymorphism and esophageal cancer (EC) remained controversial. The present meta-analysis of literatures was performed to derive a more precise estimation of the relationship. A comprehensive literature search was conducted to identify all case–control studies of Lys751Gln polymorphism and risk for two main types of EC: esophageal adenocarcinoma (EADC) and esophageal squamous cell carcinoma (ESCC). A total of 12 studies were identified to the meta-analysis, including 2,575 cases (1,294 ESCC and 1,281 EADC) and 4,951 controls (1,891 ESCC and 3,060 EADC). Random-effects or fix-effects model was used according to between-study heterogeneity. The odds ratio (OR) for the variant homozygous genotype Gln/Gln of the Lys751Gln polymorphism, compared with the wild type homozygote Lys/Lys, was 1.26, with 95% confidence interval (95% CI) 1.02–1.56, for EADC risk without between-study heterogeneity. When stratified by ethnicity, statistically significantly elevated risk was found among Chinese (Gln/Gln vs. Lys/Lys: OR 2.45, 95% CI = 1.10–5.44). However, no significant associations were found between XPD Lys751Gln polymorphism and EC risk when all studies pooled into the meta-analysis (Lys/Gln vs. Lys/Lys: OR 1.07, 95% CI = 0.88–1.28; Gln/Gln vs.us Lys/Lys: OR 1.25, 95% CI = 0.92–1.71; dominant model: OR 1.09, 95% CI = 0.90–1.33). In conclusion, this meta-analysis suggests that the Lys751Gln genetic polymorphism may be a potential biomarker of EC susceptibility in Chinese populations. And a study with the larger sample size is needed to further evaluate gene–environment interaction on XPD Lys751Gln polymorphism and EC risk.     

Association between single-nucleotide polymorphisms of selected genes involved in the response to DNA damage and risk of colon, head and neck, and breast cancers in a Polish population

Single-nucleotide polymorphisms in genes involved in DNA-damage-induced responses are reported frequently to be a risk factor in various cancer types. Here we analysed polymorphisms in 5 genes involved in DNA repair (XPD Asp312Asn and Lys751Gln,XRCC1 Arg399Gln,APE1 Asp148Glu,NBS1 Glu185Gln, andXPA G-4A) and in a gene involved in regulation of the cell-cycle (CCND1 A870G). We compared their frequencies in groups of colon, head and neck, and breast cancer patients, and 2 healthy control groups: (1) matched healthy Polish individuals and (2) a NCBI database control group. Highly significant differences in the distribution of genotypes of theAPE1, XRCC1 andCCND1 genes were found between colon cancer patients and healthy individuals. The 148AspAPE1 allele and the 399GlnXRCC1 allele apparently increased the risk of colon cancer (OR=1.9–2.3 and OR=1.5–2.1, respectively). Additionally, frequencies ofXPD genotypes differed between healthy controls and patients with colon or head and neck cancer. Importantly, no differences in the distribution of these polymorphisms were found between healthy controls and breast cancer patients. The data clearly indicate that the risk of colon cancer is associated with single-nucleotide polymorphism in genes involved in base-excision repair and DNA-damage-induced responses.     

Association of ERCC2/XPD polymorphisms and interaction with tobacco smoking in lung cancer susceptibility: a systemic review and meta-analysis

The association of the two ERCC polymorphisms, Asp312Asn and Lys751Gln, with lung cancer risk remains controversial and inconclusive. To better evaluate the potential role of the two polymorphisms and interaction with tobacco smoking in lung cancer susceptibility presented in diverse populations, we have conducted a meta-analysis based on 26 studies from 24 publications which included analyses of Asp312Asn (7121 cases, 8962 controls) and Lys751Gln (8396 cases, 10510 controls) polymorphisms. Overall, significantly elevated lung cancer risk was associated with ERCC2 312Asn allele(homozygous model: OR = 1.20[1.05–1.36], P = 0.006; recessive model: OR = 1.20[1.06–1.35], P = 0.004) and 751Gln allele(homozygous model: OR = 1.31[1.17–1.46], P < 0.00001; heterozygous model: OR = 1.11[1.04–1.19], P = 0.003; recessive model: OR = 1.23[1.11–1.37], P < 0.0001; dominant model: OR = 1.15[1.08–1.23], P < 0.0001). In ethnic subgroup analyses, significantly increased risk was associated with ERCC2 312Asn allele for both Caucasians and Asians, and 751Gln allele for both Caucasians and Latino-Americans. When stratified by smoking status, significantly elevated risk of both polymorphisms for never-smokers was detected (dominant model, OR = 1.46[1.09–1.95] and 1.57[1.19–2.08], P = 0.01 and 0.002, respectively). In conclusion, this meta-analysis suggests that the two ERCC2 polymorphisms may contribute to lung cancer susceptibility serving as low-penetrance risk factors. Extremely large-scale evidence would be necessary to confirm the effects on ethnically specific populations and gene-environment interactions.