Significant association of XPD Asp312Asn polymorphism with breast cancer in Taiwanese patients

The DNA repair gene XPD, an important caretaker of the overall genome stability, is thought to play a major role in the development of human malignancy. Polymorphic variants of XPD, at Asp312Asn (rs1799793), Lys751Gln (rs13181), and promoter C-114G (rs3810366), were chosen to be studied of their association with breast cancer susceptibility in a central Taiwanese population. In this hospital-based case-control study, the associations of XPD Asp312Asn, Lys751Gln and promoter C-114G polymorphisms with breast cancer risk were investigated. In total, 1232 patients with breast cancer and 1433 healthy controls recruited from the China Medical Hospital in Central Taiwan were genotyped. We found a significant difference in the frequency of the XPD Asp312Asn genotype, but not the XPD Lys751Gln or promoter C-114G genotypes, between the breast cancer and control groups. Those who had G/A or A/A at XPD Asp312Asn showed a 1.78-fold (95% confidence interval = 1.53-2.08) increased risk of breast cancer compared to those with G/G. As for XPD Lys751Gln or promoter C-114G, there was no difference in distribution between the breast cancer and control groups. Our findings suggest that the heterozygous and homozygous A allele of the XPD Asp312Asn may be associated with the development of breast cancer and may be a useful marker for primary prevention and anticancer intervention.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

<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.     

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.     

The association between the Lys751Gln polymorphism in the XPD gene and the risk of bladder cancer

The Lys751Gln polymorphism in the XPD gene have been suggested as a risk factor for bladder cancer, however the results were inconclusive. The aim of the current study is to assess the association by meta-analysis. A total of 15 case–control studies concerning the association between the XPD Lys751Gln polymorphism and bladder cancer risk were included in the meta-analysis. The results suggested that the Lys751Gln polymorphism was not associated with an increased risk of bladder cancer in the dominant model (OR = 1.03, 95 % CI 0.95–1.11, P = 0.53 for Lys/Gln+Gln/Gln vs. Lys/Lys) in overall analysis. In the subgroup analysis by ethnicity, no significant association was found in Caucasians or Asians. Other comparatives suggested a slight significant association between the polymorphism with the risk of bladder cancer in the recessive comparative (OR = 1.14, 95 % CI 1.02–1.29, P = 0.03). The current meta-analysis indicated that the Lys751Gln polymorphism in the XPD gene might be a risk factor for bladder cancer. In the future, more large-scale case–control studies are needed to validate our results.     

XRCC1 Arg399Gln was associated with repair capacity for DNA damage induced by occupational chromium exposure

ABSTRACT: BACKGROUND: Occupational chromium exposure may induce DNA damage and lead to lung cancer and other work-related diseases. DNA repair gene polymorphisms, which may alter the efficiency of DNA repair, thus may contribute to genetic susceptibility of DNA damage. The aim of this study was to test the hypothesis that the genetic variations of 9 major DNA repair genes could modulate the hexavalent chromium (Cr (VI))-induced DNA damage. FINDINGS: The median (P25-P75) of Olive tail moment was 0.93 (0.58-1.79) for individuals carrying GG genotype of XRCC1 Arg399Gln (G/A), 0.73 (0.46-1.35) for GA heterozygote and 0.50 (0.43-0.93) for AA genotype. Significant difference was found among the subjects with three different genotypes (P = 0.048) after adjusting the confounding factors. The median of Olive tail moment of the subjects carrying A allele (the genotypes of AA and GA) was 0.66 (0.44-1.31), which was significantly lower than that of subjects with GG genotype (P = 0.043). The A allele conferred a significantly reduced risk of DNA damage with the OR of 0.39 (95% CI: 0.15-0.99, P = 0.048). No significant association was found between the XRCC1Arg194Trp, ERCC1 C8092A, ERCC5 His1104Asp, ERCC6 Gly399Asp, GSTP1 Ile105Val, OGG1 Ser326Cys, XPC Lys939Gln, XPD Lys751Gln and DNA damage. CONCLUSION: The polymorphism of Arg399Gln in XRCC1 was associated with the Cr (VI)- induced DNA damage. XRCC1 Arg399Gln may serve as a genetic biomarker of susceptibility for Cr (VI)- induced DNA damage.     

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.     

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.     

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.     

Association between XPD Lys751Gln polymorphism and bladder cancer susceptibility: an updated and cumulative meta-analysis based on 6,836 cases and 8,251 controls

The association between xeroderma pigmentosum group D (XPD) Lys751Gln polymorphism and bladder cancer (BC) susceptibility was investigated by two meta-analyses, however, their results were contrary. We conjecture the reason might be the sample size, thus we performed this updated and cumulative meta-analysis using the Comprehensive Meta-Analysis software. We searched PubMed up to August 25th, 2013 and yielded 20 published articles with 21 case–control trails including 6,836 BC patients and 8,251 controls. The meta-analysis results showed that XPD Lys751Gln polymorphism was borderline significantly associated with BC susceptibility for overall population [Gln vs. Lys: OR 1.07, 95 % CI 1.01–1.12, P = 0.01; Gln/Gln vs. Lys/Lys: OR 1.15, 95 % CI 1.03–1.29, P = 0.01; Gln/Gln vs. (Lys/Gln + Lys/Lys): OR 1.13, 95 % CI 1.02–1.26, P = 0.02]. The cumulative meta-analysis according to the publication year showed the CI became increasingly narrower and tended to have statistical significance for the studies incessantly accumulated. In the subgroup analysis according to ethnicity, there was a significant association in Asian population and no association in Caucasian population. There was no publication bias detected. However, due to the limitations and cumulative analysis result of this meta-analysis, more well-designed and larger studies with risk factors adjusted are suggested to be performed to obtain a conclusive result on this topic.     

Associated risk of XRCC1 and XPD cross talk and life style factors in progression of head and neck cancer in north Indian population

Effective DNA repair machinery ensures maintenance of genomic integrity. Environmental insults, ageing and replication errors necessitate the need for proper DNA repair systems. Any alteration in DNA repair efficacy would play a dominant role in progression of squamous cell carcinoma of head and neck (SCCHN). Genotypes of XRCC1 gene-Arg194Trp, Arg280His, Arg399Gln and XPD Lys751Gln, by PCR-RFLP were studied in 278 SCCHN patients and an equal number of matched healthy controls residing in north India. In XRCC1 polymorphisms, Arg194Trp and Arg399Gln variants showed a reduced risk, whereas, XPD Lys751Gln variants exhibited ～2-fold increase in SCCHN risk. With XRCC1-Arg280His variants, there was no association with SCCHN risk. Arg399Gln of XRCC1 appears to have a protective role in people those consume alcohol, while XPD Lys751Gln variants indicated ～2-fold increased risk of SCCHN in all the co-variate groups. Comparison of gene-gene interaction among XRCC1 Arg280His and XPD Lys751Gln suggested enhanced risk of SCCHN by ～2.3-fold in group one and ～6.1-fold in group two. In dichotomized groups of this combination, the risk was ～2.4 times. Haplotype analysis revealed the frequency of C-G-G-G and C-A-G-G to be significantly associated with an increased risk of SCCHN. On the contrary, T-G-A-A significantly diminished the risk. CART analysis results showed that the terminal node that contains homozygous mutants of XPD Lys751Gln and XRCC1 Arg194Trp, wild type of XRCC1 Arg399Gln and homozygous mutant of XRCC1 Arg280His, represent the highest risk group. Our results demonstrate high degree of gene-gene interaction involving DNA repair genes of NER and BER pathways, namely XRCC1 and XPD. This study amply demonstrates positive association of XPD Arg751Gln polymorphism with an increased risk of SCCHN. Further, XRCC1 Arg280His variant though dormant individually, may also contribute to the development of cancer in combination with XPD Arg751Gln.     

Influence of GSTM1 null and low repair XPC PAT+ on anti-B[a]PDE-DNA adduct in mononuclear white blood cells of subjects low exposed to PAHs through smoking and diet

The influence of low-activity NER genotypes (XPC PAT-/+, XPA-A23G, XPD Asp312Asn, XPD Lys751Gln) and GSTM1 (active or null) was evaluated on anti-benzo[a]pyrene diol epoxide-(B[a]PDE)-DNA adduct formed in the lymphocyte plus monocyte fraction (LMF). The sample population consisted of 291 healthy subjects with low exposure to polycyclic aromatic hydrocarbons (PAHs) (B[a]P) through their smoking (n=126 smokers) or dietary habits (n=165 non-smokers with high (>or=52 times/year) consumption of charcoaled meat or pizza). The bulky anti-B[a]PDE-DNA adduct levels were detected by HPLC/fluorescence analysis and genotypes by PCR. Anti-B[a]PDE-DNA was present (>or=0.5 adducts/10(8) nucleotides) in 163 (56%) subjects (median (range) 0.77 (0.125-32.0) adducts/10(8) nucleotides), with smokers showing a significantly higher adduct level than non-smokers with high consumption of PAH-rich meals (P<0.01). Our exposed-sample population with unfavourable XPC PAT+/- or +/+ and GSTM1 null genotypes has the significantly highest adduct level (P<0.01). Taking into account tobacco smoke and diet as sources of exposure to B[a]P, low-activity XPC PAT+ shows a major role in smokers (P<0.05) and GSTM1 null in non-smokers with frequent consumption of PAH-rich meals (P<0.01). The modulation of anti-B[a]PDE-DNA adduct in the LMF by GSTM1 null and low-activity XPC PAT+ polymorphisms may be considered as potential genetic susceptibility factors that can modify individual responses to low PAH (B[a]P) genotoxic exposure, with the consequent risk of cancer in the general population.