Genetic polymorphisms and possible gene-gene interactions in metabolic and DNA repair genes: effects on DNA damage

We investigated in a central European population, the association between genetic polymorphisms in several genes coding for xenobiotic metabolizing enzymes (CYP1A1, CYP2E1, EPHX1, GSTP1, GSTM1 and GSTT1) and in DNA repair genes (XPD, XPG, XPC and XRCC1) and the levels of single-strand breaks (SSBs) and SSB endonuclease III sensitive sites (endoIII sites) in peripheral blood lymphocytes. No significant differences in the mean levels of SSBs and endoIII sites after stratification for main confounders and occupational exposure were observed in the studied population. Significantly higher levels of SSBs were observed in individuals bearing the wild-type alleles (AA) (0.75+/-0.51SSB/10(9)Da) and heterozygous (AC) genotypes (0.67+/-0.49SSB/10(9)Da) compared to those with homozygous XPD (CC) genotype (0.43+/-0.28SSB/10(9)Da, P=0.033). A moderate increase in the levels of SSBs was also found in individuals with the homozygous XPG exon 15 wild type (GG) and heterozygous (GC) genotypes in comparison to those with the homozygous (CC) genotype (P=0.066) and in individuals with low activity EPHX1 genotype in comparison to those with high activity genotype. Nevertheless, these differences were not statistically significant. No other significant association was found. When gene-gene interactions were evaluated, a combination of EPHX1 activity genotypes with that of either XPD or XPG significantly (P=0.003 and 0.016, respectively) modulated SSB levels resulting in a three-fold difference between the "protective" and the "adverse" genotype-combinations. Almost three-fold differences in SSB levels were found between the "protective" and the "adverse" genotype-combinations of EPHX1 activity genotype and GSTM1 or GSTT1 genotypes, respectively. In conclusion, our results suggest a relation between markers of genotoxicity and polymorphisms in genes coding for xenobiotic metabolizing and DNA repair enzymes as well as a modulating effect of combinations of these polymorphisms.     

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.     

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.     

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.     

Polymorphisms of phase II xenobiotic-metabolizing and DNA repair genes and in vitro N-ethyl-N-nitrosourea-induced O6-ethylguanine levels in human lymphocytes

This study tested the hypothesis that genetic variants of phase II detoxification enzymes and DNA repair proteins affect individual response to DNA damage from alkylating agents. In 171 healthy individuals, an immunoslot blot assay was used to measure O6-ethylguanosine (O6-EtGua) adduct levels in peripheral blood lymphocytes treated with N-ethyl-N-nitrosourea (ENU) in vitro. The genotypes of GSTM1, GSTT1, GSTP1 I(105)V and A(114)V, MGMT L(84)F and I(143)V, XPD D(312)N and K(751)Q, and XRCC3 T(241)M were determined. Demographic and exposure information was collected by in-person interview. Student's t-test, analysis of (co)variance, and multiple linear regression models were used in statistical analyses. The mean and median (range) O6-EtGua levels were 94.6 and 84.8 (3.2-508.1)fmol/g DNA, respectively. The adduct level was significantly lower in people who smoked >or=25 years than that in never-smokers (square-root transformed mean values 8.20 versus 9.37, P=0.03). Multiple linear regression models revealed that GSTT1 (beta=-2.36, P=0.009) polymorphism was a significant predictor of the level of adducts in 82 never-smokers, whereas the number of years smoked (beta=-0.08, P=0.005) and XRCC3 T(241)M (beta=2.22, P=0.007) in 89 ever-smokers. The association between GSTP1 I(105)V, MGMT I(143)V, and XPD D(312)N with the level of adducts was not conclusive. Each polymorphism could explain 2-10% of the variation of the adduct level. These observations suggest that GSTT1 null and XRCC3 T(241)M polymorphism may have some functional significance in modulating the level of ENU-induced DNA damage and these effects are smoking-dependent. Results from this exploratory study need to be confirmed in other experimental systems.     

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.     

Genetic polymorphisms of the DNA repair gene and risk of nasopharyngeal carcinoma

Context: X-ray repair cross-complementing groups 1 and 3 (XRCC1 and XRCC3) and xeroderma pigmentosum group D (XPD) are mainly involved in base excision repair, homologous recombination repair, and nucleotide excision repair of DNA repair pathways, respectively. Previous studies have demonstrated that their gene polymorphisms were associated with some cancer susceptibility. Objective and design: To investigate the effect of XPD Lys751Gln, XRCC1 Arg399Gln, Arg194Trp, Arg280His, and XRCC3 Thr241Met polymorphisms on the risk of nasopharyngeal carcinoma (NPC), a population-based case-control study of 153 NPC patients and 168 healthy controls among Sichuan population was conducted. Results: Our results showed that XRCC1 codon 194 Trp allele was associated with an increased risk of NPC (odds ratio [OR] = 1.828, 95% confidence interval [CI]: 1.286-2.598), and XPD codon 751Gln allele was associated with a borderline decrease of NPC (OR = 0.600, 95% CI: 0.361-1.000); combination analysis showed that individuals with both putative genotypes of XPD codon 751 Lys/Lys and XRCC1 codon 194 Arg/Trp or Trp/Trp have a significantly elevated risk of NPC (OR = 2.708, 95% CI: 1.338-5.478). Conclusion: The results indicated that XRCC1 codon 194 Trp allele and XPD codon 751 Lys allele may be contributing factors in the risk of NPC.     

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.     

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.     

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.     

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.     

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.     

The investigation of DNA repair polymorphisms with histopathological characteristics and hormone receptors in a group of Brazilian women with breast cancer

The association of tumor differentiation and estrogen receptor expression with the prognosis of breast cancer has been well established. Nevertheless, little is yet reported about the association of morphological characteristics of the tumor, estrogen receptor status and polymorphisms in low penetrance genes. The aim of the present study was to investigate a possible association between DNA repair gene polymorphisms (XRCC1, XPD, XRCC3, and RAD51) with histological type, grade and hormone receptor expression in a series of breast cancers. A cross-sectional study was carried out to evaluate 94 women with breast carcinoma, who had already been selected and included in a study on the association of DNA repair gene polymorphisms. For immunohistochemistry, formalin-fixed, paraffin-embedded tissue samples from breast tumors were consecutively retrieved from the histopathology files of our institution. DNA obtained from blood samples of the same patients was investigated for the presence of the following polymorphisms: Arg-399Gln located in the XRCC1 gene; 135C/G located in the RAD51 gene; Lys751Gln located in the XPD gene and Thr241Met located in the XRCC3 gene. Polymorphisms were considered to be independent variables and hormone receptor expression and the morphological characteristics of the tumors comprised the dependent variables. No statistically significant association was found between gene polymorphisms and hormone receptor status. The association between XRCC1-Arg399Gln polymorphism and ductal carcinoma was statistically significant (P = 0.02). The association of the XPD-Lys751Gln polymorphism with histological grade was also tatistically significant (p = 0.05). In conclusion, the XRCC1 genotype was found to be associated with ductal carcinoma histotypes and XPD genotype with low histological grade, which is the most frequent pattern of sporadic breast carcinomas.     

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.     

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.     

An association between DNA repair gene polymorphisms and survival in patients with resected non-small cell lung cancer

DNA repair genetic polymorphisms have been studied extensively in relation to lung cancer susceptibility, but much less is known about their role in clinical outcome modulation. In this report, we examined effect of the XPA −4G>A, XPD Asp312Asn, Leu751Gln, hHR23B Ala249Val, XPG Asp1104His, XRCC1 Arg399Gln, XRCC2 −4234G>C and XRCC3 Thr241Met polymorphisms on overall survival in 162 patients with resected non-small cell lung cancer (NSCLC). The XRCC3 Met/Met genotype was significantly associated with increased risk of death among all patients and men in uni- and multivariate analyses. The risk was higher for adenocarcinoma patients possessing the XRCC3 Met/Met or XRCC1 Gln/Gln genotypes, although their frequency was small. The XRCC1 399Gln allele was also associated with poor prognosis in stage II–IIIA and among older individuals. Men homozygous for the XPD 312 Asn/Asn had significantly better survival with the risk of death being at borderline significance in uni- and multivariate models. Younger cases and ever smokers smoking less than median pack-years showed significantly increased risk of death associated with the XPA −4A allele. A presence of one or two XRCC2 −4234C alleles had a protective effect in males and ever smokers with lower cumulative smoking dose, although the CC genotype was rarely observed. When number of combined risk alleles was considered, we found that carriers of >4 adverse alleles were at significantly increased risk of death in uni- and multivariate models. Therefore, our results indicate that selected genetic polymorphisms in DNA repair genes may influence overall survival in resected NSCLC.     

The peculiarities of polymorphism of XPD and XRCC1 repair genes in cells of Down and Ehlers-Danlo syndrome patients characterized by increased radiosensitivity

Codon 312 and 751 polymorphisms ofXPD gene and codon 399 polymorphism of XRCC1 gene of peripheral blood lymphocytes in patients with Down syndrome (DS) (46 individuals), Ehlers-Danlo syndrome (EDS) (47 individuals) and in a group of healthy donors (control) (40 individuals) have been studied. Frequency of XPD genotype (G312G) coding for the most effectively functioning form of XPD protein was lower in patients with DS (26%) than in a group of healthy donors (42.5%) (p = 0.035), whereas no significant differences with the control were revealed for this codon in patients with EDS. No patients with XPD genotype (C751C) (p = 0.036) were revealed in a group of EDS patients, while this genotype was found in 16% of a group of healthy donors and in 17% of patients with DS. The trend of XRCC1 genotype frequency reduction (A399A) (p = 0.085) in EDS patients (3.9%) compared with the group of healthy donors (13.5%) and DS patients (13.3%) has been obtained. These data show that polymorphisms of the excision repair genes under study are accompanied by an elevated individual radio sensitivity in patients with DS. Genes investigated (their polymorphic variants) did not participate in the mechanisms for radio sensitive phenotype formation in EDS patients.     

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.     

<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.     

The evaluation of association between polymorphisms of DNA excision repair enzyme genes and risk of malignant tumors development in Siberian Group of Chemical Enterprises workers

There was analyzed single nucleotide polymorphisms of DNA excision repair enzyme genes hOGG, XPD, XPG, XRCC1 in 98 Siberian Group of Chemical Enterprises cancer patients and 148 healthy donors. No association was observed between the analyzed polymorphisms and malignant tumors in both control and subgroup (under study) of persons exposed to occupational ionizing radiation. Heterozygosis for the genes hOGG and XPD was found to be a protective factor to malignant tumors in exposed persons: the odds ratio = 0.42 (95% CI 0.18-0.98; p = 0.044) for the 326Ser/Cys genotype of the hOGG gene and 0.48 (95% CI 0.23-0.99; p = = 0.047) the 751Lys/Gln genotype of the XPD gene. The data obtained show a possible modifying role of the hOGG and XPD gene polymorphisms for malignant tumors risk in exposed persons.