XPC Lys939Gln Research Articles

Association of gene polymorphisms with biological features of gastric cancer

Aim of the investigation. To evaluate associations of polymorphic variants of TNF (G308A), XPC (Lys939Gln), MTHFR (Ala222Val) genes with some biological features of gastric cancer. Materials and Methods. We evaluated polymorphic gene variants in 74 patients with verified gastric cancer or gastriesophageal junction cancer (Siewert III). Genotyping was performed by DNA isolation from venous blood leukocytes of the subjects followed by PCR with electrophoretic detection of the result. The association of polymorphic variants of genes with such biological features of the tumor as localization of the process, morphological type, degree of differentiation, type of tumor growth, presence or absence of lymphovascular or perineural invasion was evaluated. Results. Lys/Gln genotype of XPC gene (Lys939Gln) are 3.3 times more likely to develop gastric body cancer (p=0.04). Genotype GG of TNF gene (G308A) 5.3 times increases the development of gastric adenocarcinoma in comparison with other histological types (p=0.018), genotype GA of the same gene 5.2 times more often develop tumor with high-grade differentiation degree (p=0.032). Val/Val genotype of the MTHFR gene (Ala222Val) are significantly less likely to develop lymphatic/vascular invasion compared to carriers of the other genotype (p=0,029). Conclusion. The obtained data suggest that the genetic status of the patient itself may affect the biological characteristics of gastric cancer, which in turn may lead to a change in the patient’s treatment tactics.

The Role of DNA Repair (XPC, XPD, XPF, and XPG) Gene Polymorphisms in the Development of Myeloproliferative Neoplasms.

Background and Objectives: Several polymorphisms have been described in various DNA repair genes. Nucleotide excision DNA repair (NER) detects defects of DNA molecules and corrects them to restore genome integrity. We hypothesized that the XPC, XPD, XPF, and XPG gene polymorphisms influence the appearance of myeloproliferative neoplasms (MPNs). Materials and Methods: We investigated the XPC 1496C>T (rs2228000, XPC Ala499Val), XPC 2920A>C (rs228001, XPC Lys939Gln), XPD 2251A>C (rs13181, XPD Lys751Gln), XPF-673C>T (rs3136038), XPF 11985A>G (rs254942), and XPG 3507G>C (rs17655, XPG Asp1104His) polymorphisms by polymerase chain reaction-restriction fragment length polymorphism analysis in 393 MPN patients [153 with polycythemia vera (PV), 201 with essential thrombocythemia (ET), and 39 with primary myelofibrosis (PMF)] and 323 healthy controls. Results: Overall, we found that variant genotypes of XPD 2251A>C were associated with an increased risk of MPN (OR = 1.54, 95% CI = 1.15-2.08, p = 0.004), while XPF-673C>T and XPF 11985A>G were associated with a decreased risk of developing MPN (OR = 0.56, 95% CI = 0.42-0.76, p < 0.001; and OR = 0.26, 95% CI = 0.19-0.37, p < 0.001, respectively). Conclusions: In light of our findings, XPD 2251A>C polymorphism was associated with the risk of developing MPN and XPF-673C>T and XPF 11985A>G single nucleotide polymorphisms (SNPs) may have a protective role for MPN, while XPC 1496C>T, XPC 2920A>C, and XPG 3507G>C polymorphisms do not represent risk factors in MPN development.

Association of polymorphisms in nucleotide excision repair pathway genes with susceptibility to cutaneous melanoma.

The effects of single nucleotide polymorphisms (SNPs) at nucleotide excision repair (NER) pathway on susceptibility to cutaneous melanoma (CM) are of great interest. To date, several epidemiological studies have evaluated whether the XPC, XPD, XPG and XPF polymorphisms are associated with CM. However, those studies results are controversial or inconclusive. Therefore, we conducted a study to evaluate the association of seven frequently investigated NER pathway polymorphisms with CM risk. A total of 150 patients dia-gnosed with CM and 150 healthy controls were enrolled in the study. Seven SNPs in the NER pathway including XPC (Lys939Gln and Ala499Val), XPD (Lys157Gln, Asp272Asn, and Arg751Arg), XPG (Asp1104His) and XPF (Arg415Gln) were analyzed by polymerase chain reaction restriction fragment length polymorphism assay. There was no a significant association between XPC Lys939Gln, Ala499Val; XPD Asp272Asn, Arg751Arg, Arg751Arg; XPF Arg415Gln; and XPG Asp1104His polymorphisms and an increased risk of CM. This study results revealed that the XPC, XPD, XPG and XPF polymorphisms were not risk factor for susceptibility to CM. However, more well-designed with larger sample size studies in different populations are necessary to further evaluate and validate our results. Future studies which take into account gene-gene and gene-environment interactions are warranted for more precise evidence and further elucidation of the underlying mechanism of CM.

Polymorphisms in XPC gene and risk for prostate cancer.

Single nucleotide polymorphisms (SNP) in repair gene DNA such as XPC gene can reduce the DNA repair capacity (DRC). Reduced DRC induce genetic instability and may increase the susceptibility to prostate cancer (PC). We conducted a case-controls study to examine the relationship between XPC Lys939Gln and XPC-PAT polymorphisms and the risk for prostate cancer in Tunisian population. We have also correlated molecular results with clinical parameters (Gleason score and TNM status) and lifestyle factors (tobacco status, alcohol consumption, and exposition to professional risk factors) of prostate cancer patients. We have found that the XPC Lys939Gln polymorphism was not associated with a risk of prostate cancer. However the XPC PAT I/I genotype was found to be associated with 3.83-fold increased risk of prostate cancer compared to controls (p = 0.00006; OR 3.83; 95% CI (1.83-8.05)). The test of linkage disequilibrium showed that XPC-PAT polymorphism is in linkage disequilibrium with XPC Lys939Gln variants. The combined analysis of XPC Lys939Gln and XPC-PAT variants showed that patients who inherited (Lys/Gln + PAT D/D) genotypes were protected against prostate cancer development compared to controls. In the other hand, no significant association has been found between XPC polymorphisms and clinical parameters or between XPC polymorphisms and lifestyle factors.

XPC Polymorphism and Risk for Lung Cancer in North Indian Patients Treated with Platinum Based Chemotherapy and Its Association with Clinical Outcomes.

Xeroderma pigmentosum complementation group C plays an important role in the human repair system. As reported in previous studies its polymorphism are associated with lung cancer susceptibility. The purpose of this study is to investigate the association of XPC gene with lung cancer susceptibility, overall response and clinical outcomes amongst North Indians. A hospital based study of 370 lung cancer cases and 370 healthy controls was conducted and genotypes were determined using PCR-RFLP assay. Results were assessed using logistic linear regression adjusted for age, sex and smoking status. Survival analysis was conducted using Kaplan-Meier survival analysis and Cox regression analysis. The treatment outcomes of 167 lung cancer patients treated with platinum based chemotherapy were evaluated.The mutant genotypic variant of XPC Lys939Gln has been associated with elevated risk of lung cancer(OR:2.30;95%CI:1.41-3.73;p=0.0007) whereasXPC Ala499Val showed a highly protective effect (OR:0.25;95%CI:0.10-0.63;p=0.003). The mutant genotype of XPC Lys939Gln presented a higher risk of developing lung cancer in heavy smokers (OR: 3.71; 95%CI:1.46-9.45; p=0.005). The survival analysis presented that heterozygous genotype showed least survival in comparison with mutant genotype inXPCAla499Val genetic variant whereas no significant association was observed in XPC Lys939Gln. In conclusion, XPC Lys939Gln is associated with significant risk towards the lung cancer whereas on contrary XPC Ala499Val shows a protective effect.

A meta-analysis of XPC Lys939Gln polymorphism and melanoma susceptibility.

It has been reported that polymorphisms of XPC Lys939Gln may affect the risk of melanom. However, the results have been inconsistent.We performed a comprehensive meta-analysis to determine the association between XPC Lys939Gln polymorphism and melanoma susceptibility. Based on comprehensive searches of the MEDLINE, EMBASE and ISI Web of knowledge, China National Knowledge Infrastructure (CNKI) and Wanfang Database, we identified eligible studies about the association between XPC Lys939Gln polymorphism and melanoma risk. A total of 4631 cases and 5111 controls in studies were included in this meta-analysis. All studies were conducted in Caucasian populations. Allele model (Gln vs. Lys: P = 0.22; OR = 1.07, 95% CI = 0.96-1.18), and homozygous model (Gln/Gln vs. Lys/Lys: P = 0.66; OR = 1.03, 95% CI = 0.91-1.17) did not show increased risk of developing melanoma. Similarly, dominant model Gln/Gln and Gln/Lys vs. Lys/Lys: P = 0.07; OR = 1.17, 95% CI = 0.99-1.40) and recessive model (Gln/Gln vs. Gln/Lys and Lys/Lys: P = 0.67; OR = 1.03, 95% CI = 0.90-1.19) failed to show increased risk of developing melanoma. Our pooled data suggest that there was no evidence for a major role of XPC Lys939Gln polymorphism in the pathogenesis of melanoma.

Prognostic significance of head and neck squamous cell carcinoma repair gene polymorphism.

The aims of this study were to analyze the polymorphisms XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, XPC Lys939Gln, ERCC1 Asn118Asn, and RAD51 -98G>C and to verify their influence on radiotherapy response and prognosis of patients with head and neck squamous cell carcinoma (HNSCC). Peripheral blood DNA was extracted from 311 patients and analyzed by PCR-RFLP. Our results showed that in irradiated oral and oropharyngeal patients, the 939Gln allele increased 6-fold local disease relapse risk (OR = 6.04; CI = 1.47-24.88) and over 2-fold the earliness of relapse (HR = 2.63; CI = 1.04-6.70). As for the XRCC3 polymorphism, multivariate analysis showed that the 241Met allele increases over 33-fold local relapse risk (OR = 33.64; CI = 3.23-350.85), over 12-fold earliness of relapse (HR = 12.55; CI = 2.47-63.73) and over 3-fold earliness of death (HR = 3.04; CI = 1.08-8.61). For polymorphism RAD51 -98, multivariate analysis showed that allele C increases over 3-fold the risk of relapse (OR = 3.13; CI = 1.12-8.78) and over 2-fold the earliness of relapse (HR = 2.84; CI = 1.25-6.47). For polymorphism XRCC1 Arg399Gln, multivariate analysis showed that the 399Gln allele increased the risk of local disease relapse for irradiated oral and oropharyngeal patients (OR = 3.35; CI = 1.10-10.13) by over 3-fold. Based on these results, we suggest that these polymorphisms may be useful markers of prognosis in HNSCC.

Polymorphisms in XPC, XPD and XPG DNA repair genes and leukemia risk in a Tunisian population

Human DNA repair mechanisms protect the genome from DNA damage caused by endogenous and environmental agents. Polymorphisms in DNA repair genes and differences in repair capacity between individuals have been widely reported in different cancers. In this study we aimed to evaluate the associations between XPC Lys939Gln (rs2228001), XPD Lys751Gln (rs13181) and XPG Asp1104His (rs17655) polymorphisms and leukemia risk in a Tunisian population. Genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) in 206 patients with leukemia and 206 healthy controls. We found increased risk of leukemia among subjects carrying the XPC 939Gln/Gln genotype (odds ratio [OR] = 2.48, 95% confidence interval [CI] = 1.353–4.560, p = 0.0042). Moreover, in subgroup analysis according to clinical types, patients with chronic myeloid leukemia (CML) showed a higher risk than patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) (OR = 3.87, 95% CI = 1.820–8.237, p = 0.0003). However, the XPD 751Gln allele may be protective against CML and AML development, and no significant differences in genotype frequencies were observed for the XPG gene between patients and controls. Further studies with larger samples and risk factor information are needed.

XPC Lys939Gln polymorphism contributes to colorectal cancer susceptibility: evidence from a meta-analysis.

BackgroundPublished studies investigating the association between XPC Lys939Gln polymorphism and colorectal cancer (CRC) risk reported inconclusive results. We performed a meta-analysis to derive a precise estimation of the relationship.MethodsA comprehensive literature search was done in databases PubMed, EMBASE, and Cochrane library up to December 2013. The association between XPC Lys939Gln polymorphism and CRC risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs).ResultsEight studies with 3,301 cases and 4,177 controls were included in the meta-analysis. We observed that the XPC Lys939Gln polymorphism was correlated with an increased CRC risk when all studies were pooled into the meta-analysis (Gln/lys vs. Lys/Lys: OR = 1.293, 95% CI 1.169–1.430, P = 0.000; Gln/Gln + Gln/lys vs. Lys/Lys: OR = 1.260, 95% CI 1.145–1.388, P = 0.000). In stratified analyses by ethnicity, smoking, and study quality, significant increased CRC risk was found in Asians (Gln/lys vs. Lys/Lys: OR = 1.345, 95% CI 1.187–1.523, P = 0.000; Gln/Gln + Gln/lys vs. Lys/Lys: OR = 1.317, 95% CI 1.170–1.484, P = 0.000), nonsmokers (Gln/Gln + Gln/lys vs. Lys/Lys: OR = 1.286, 95% CI 1.020–1.622, P = 0.033), and high quality studies. In subgroup analysis by source of control, significant increased CRC risk was found in both hospital-based studies and population-based studies. However, in subgroup analysis according to cancer location, no any significant association was detected.ConclusionsThis meta-analysis suggests that the XPC is a candidate gene for CRC susceptibility. The XPC Lys939Gln polymorphism may play an important role in CRC development among Asians and nonsmokers. Further large and well-designed studies are needed to confirm this association.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1665902729125948

XPC Lys939Gln and Ala499Val polymorphisms in colorectal cancer susceptibility: a meta-analysis of case–control studies

The XPC Lys939Gln and Ala499Val polymorphisms were likely to be involved with the development of colorectal cancer. However, there had been inconsistent reports of association. This meta-analysis of literatures was performed to draw a more precise estimation of the relationship. We systematically searched PubMed, Embase and Web of Science for relevant articles with a time limit of December 2012. The strength of association between the XPC Lys939Gln and Ala499Val polymorphisms and colorectal cancer susceptibility were assessed by odds ratio (OR) with the corresponding 95% confidence interval (95% CI). This meta-analysis including six case-control studies evaluated the associations between the two XPC polymorphisms (Lys939Gln, Ala499Val) and colorectal cancer susceptibility. For XPC Lys939Gln, no obvious associations were found for all genetic models [CC vs AA: OR (95% CI)=1.12 (0.94-1.32); CA vs AA: OR (95% CI)=1.08 (0.94-1.24); the dominant model: OR (95% CI)=1.09 (0.97-1.23); the recessive model: OR (95% CI)=1.07 (0.92-1.25)]. For XPC Ala499Val, no obvious associations were also not found for all genetic models [TT vs CC: OR (95% CI)=0.84 (0.65-1.10); CT vs CC: OR (95% CI)=1.00 (0.86-1.15); the dominant model: OR (95% CI)=0.98 (0.85-1.12); the recessive model: OR (95% CI)=0.87 (0.67-1.12)]. This meta-analysis suggested that both the XPC Lys939Gln and Ala499Val polymorphisms were not risk factors for increasing colorectal cancer.

Polymorphisms of DNA repair genes and lung cancer in chromium exposure.

Chromium is a well known carcinogen involved in the lung cancer development. Polymorphism of some of the DNA repair genes may be associated with elevated risk of cancerous transformation. In the present study, we investigated the polymorphisms of the following selected members of the base and nucleotide excision repair genes: XPC (Lys939Gln), XPD (Lys751Gln), XRCC1(Arg399Gln), and hOGG1(Ser326Ser), and the risk they present toward the development of lung cancer, with emphasis on the effect of chromium exposure. We analyzed 119 individuals; 50 patients exposed to chromium with diagnosed lung cancer and 69 healthy controls. Genotypes were determined by a PCR-RFLP method. We found a significantly increased risk of lung cancer development in XPD genotype Lys/Gln (OR=1.94; 95% CI=1.10-3.43; p=0.015) and in the gene combinations: XPD Lys/Gln+XPC Lys/Gln (OR=6.5; 95% CI=1.53-27.49; p=0.009) and XPD Lys/Gln+XPC Gln/Gln(OR=5.2; 95% CI=1.07-25.32; p=0.04). In conclusion, gene polymorphisms in the DNA repair genes may underscore the risk of lung cancer development in the chromium-exposed individuals.

Polymorphisms of the XPC gene may contribute to the risk of head and neck cancer: a meta-analysis

Polymorphisms of the XPC gene have been reported to be associated with an increased risk of head and neck cancer (HNC), though the exact biological effect is still unclear. Genetic association studies (GAS) investigating the associations between three common polymorphisms (PAT, Lys939Gln, and Ala499Val) of the XPC gene and HNC risk have produced contradictory and inconclusive results. The aim of this meta-analysis is to evaluate the contributions of these polymorphisms to the risk of HNC. A literature search was conducted in the PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure databases to indentify eligible studies. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to evaluate the strength of the associations under a fixed- or random-effect model according to heterogeneity test. Twelve case-control studies were included in this meta-analysis with a total of 3,078 HNC patients and 4,311 healthy controls. For XPC PAT, a significant overall association was found under all major genetic models. Stratified analyses further indicated significant associations in the Caucasian, population-based, non-PCR-RFLP, esophageal cancer and oral cancer subgroups. For XPC Lys939Gln, few significant results were found in either the overall analysis or stratified analyses. For XPC Ala499Val, the combined results revealed a significantly increased risk of HNC for carriers of the 499Val allele. This meta-analysis shows that the XPC PAT and Ala499Val polymorphisms may be associated with an increased risk of HNC, while XPC Lys939Gln may not be associated with HNC risk. Despite some limitations, this meta-analysis establishes solid statistical evidence for an association between XPC genetic polymorphisms and HNC risk that warrants further validation.

Quantitative assessment of the association between XPC Lys939Gln polymorphism and cutaneous melanoma risk

Previous studies evaluating the association between XPC Lys939Gln polymorphism and cutaneous melanoma risk reported conflicting findings. We searched PubMed and Embase databases up to May 16, 2013 to identify eligible studies on the association between XPC Lys939Gln polymorphism and cutaneous melanoma risk. Finally, a total of seven case-control studies including 3,971 cases of cutaneous melanoma and 5,873 controls were included in the meta-analysis. Statistical analysis was performed with STATA version 11.0. Odds ratios (ORs) with 95 % confidence intervals (95 % CIs) were used to assess the strength of the association. Overall, there was no association between XPC Lys939Gln polymorphism and cutaneous melanoma risk under all five genetic models (Gln vs. Lys: OR = 1.11, 95 % CI = 0.98-1.26, P = 0.10; GlnGln vs. LysLys: OR = 1.26, 95 % CI = 0.98-1.61, P = 0.07; LysGln vs. LysLys: OR = 1.04, 95 % CI = 0.88-1.22, P = 0.64; GlnGln/LysGln vs. LysLys: OR = 1.10, 95 % CI = 0.92-1.31, P = 0.29; GlnGln vs. LysLys/LysGln: OR = 1.19, 95 % CI = 0.99-1.43, P = 0.06). Subgroup analysis in Caucasians showed that there was an obvious association between XPC Lys939Gln polymorphism and cutaneous melanoma risk in Caucasians (GlnGln vs. LysLys/LysGln: OR = 1.12, 95 % CI = 1.00-1.25, P = 0.05). Sensitivity analysis by omitting one study in turns showed that the significance of the pooled ORs was not stable. In addition, there was some evidence of publication bias in the meta-analysis, and meta-analyses of the studies with large sample size did not find the obvious association between XPC Lys939Gln polymorphism and cutaneous melanoma risk in Caucasians. Therefore, there is little evidence for the association between XPC Lys939Gln polymorphism and cutaneous melanoma risk.

Associations of ABCB1 and XPC Genetic Polymorphisms with Susceptibility to Colorectal Cancer and Therapeutic Prognosis in a Chinese Population

Associations between ABCB1 and XPC genetic polymorphisms and risk of developing colorectal cancer (CRC) as well as clinical outcomes in CRCs with chemotherapy were investigated. A case-control study was performed on the ABCB1 C3435T, G2677T/A and XPC Lys939Gln polymorphisms in 428 CRC cases and 450 hospital- based, age and sex frequency-matched controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays. We observed that the ABCB1 3435CT or CC+CT variants were significantly linked with increasing risk of developing CRC (adjusted OR (95% CI): 1.814 (1.237-2.660), P=0.0022; adjusted OR (95% CI): 1.605 (1.117-2.306), P=0.0102, respectively). Moreover, the distribution frequency of XPC AC genotype or AC+CC genotypes also showed a tendency towards increasing the suscepbility for CRC (P=0.0759 and P=0.0903, respectively). Kaplan-Meier curves showed that the ABCB1 C3435T variant was associated with a tendency toward longer progression-free survival (PFS) (n=343, Log-rank test: P=0.063), and the G2677T/A variant genotypes (GT+TT+GA+AA) with a tendency for longer OS in postoperative oxaliplatin-based patients (n=343, Log-rank test: P=0.082). However, no correlation of the XPC Lys939Gln polymorphism was found with PFS and OS in patients with postoperative oxaliplatin-based chemotherapy (n=343). Our study indicated that ABCB1 polymorphisms might be candidate pharmacogenomic factors for the prediction of CRC susceptibility, but not for prognosis with oxaliplatin chemosensitivity in CRC patients.

DNA repair genes polymorphism and lung cancer risk with the emphasis to sex differences

Polymorphisms in nucleotide and base excision repair genes are associated with the variability in the risk of developing lung cancer. In the present study, we investigated the polymorphisms of following selected DNA repair genes: XPC (Lys939Gln), XPD (Lys751Gln), hOGG1 (Ser326Cys) and XRCC1 (Arg399Gln), and the risks they present towards the development of lung cancer with the emphasis to gender differences within the Slovak population. We analyzed 761 individuals comprising 382 patients with diagnosed lung cancer and 379 healthy controls. Genotypes were determined by polymerase chain reaction/restriction fragment length polymorphism method. We found out statistically significant increased risk for lung cancer development between genders. Female carrying XPC Gln/Gln, XPC Lys/Gln+Gln/Gln and XRCC1 Arg/Gln, XRCC1 Arg/Gln+Gln/Gln genotypes had significantly increased risk of lung cancer corresponding to OR=2.06; p=0.04, OR=1.66; p=0.04 and OR=1.62; p=0.04, OR=1.69; p=0.02 respectively. In total, significantly increased risk of developing lung cancer was found in the following combinations of genotypes: XPD Lys/Gln+XPC Lys/Lys (OR=1.62; p=0.04), XRCC1 Gln/Gln+hOGG1 Ser/Ser (OR=2.14; p=0.02). After stratification for genders, the following combinations of genotype were found to be significant in male: XPD Lys/Gln+XPC Lys/Lys (OR=1.87; p=0.03), XRCC1 Arg/Gln+XPC Lys/Lys (OR=4.52; p=0.0007), XRCC1 Arg/Gln+XPC Lys/Gln (OR=5.44; p<0.0001). In female, different combinations of the following genotypes were found to be significant: XRCC1 Arg/Gln+hOGG1 Ser/Ser (OR=1.98; p=0.04), XRCC1 Gln/Gln+hOGG1 Ser/Ser (OR=3.75; p=0.02), XRCC1 Arg/Gln+XPC Lys/Gln (OR=2.40; p=0.04), XRCC1 Arg/Gln+XPC Gln/Gln (OR=3.03; p=0.04). We found out decreased cancer risk in genotype combinations between female patients and healthy controls: XPD Lys/Lys+XPC Lys/Gln (OR=0.45; p=0.02), XPD Lys/Gln+XPC Lys/Lys (OR=0.32; p=0.005), XPD Lys/Gln+XPC Lys/Gln (OR=0.48; p=0.02). Our results did not show any difference between pooled smokers and non-smokers in observed gene polymorphisms in the association to the lung cancer risk. However, gender stratification indicated the possible effect of heterozygous constitution of hOGG1 gene (Ser/Cys) on lung cancer risk in female non-smokers (OR=0.20; p=0.01) and heterozygous constitution of XPC gene (Lys/Gln) in male smokers (OR=2.70; p=0.01).

Polymorphisms in BER and NER pathway genes: Effects on micronucleus frequencies among vinyl chloride-exposed workers in northern China

In this study, a group of 317 workers occupationally exposed to vinyl chloride monomer and 166 normal, unexposed referents in Shandong province (Northern China) were examined for chromosomal damage in peripheral lymphocytes using the cytokinesis-blocked micronucleus (CB-MN) assay. The exposure group (3.47±2.65)‰ showed higher micronucleus frequency than the unexposed workers (2.51±1.96)‰ (P<0.01). We explored the relationship between genetic polymorphisms of XRCC1 (−77C/T, Arg194Trp, Arg280His, Arg399Gln), APE1 Asp148Glu, XPA Ala23Gly, XPC.PAT, XPC Ala499Val, XPC Lys939Gln, XPF 5′-UTR T2063A, XPG Exon15 G-C, ERCC13′-UTR C8092A and susceptibility of chromosomal damage in all the subjects. It was found that XRCC1 −77, XRCC1 280, APE1148, XPC.PAT, XPG Exon15 G-C, and ERCC13′-UTR C8092A polymorphisms showed no significant associations with micronucleus frequency in unexposed workers. However, among the exposed workers individuals with XRCC1 (−77C/T, Arg194Trp, Arg280His, Arg399Gln) polymorphisms had a significantly higher micronucleus frequency as seen in mean frequency ratios (FR) compared with their homozygous wild-type genotypes (FR=1.21, 95% CI: 1.05–1.39; P<0.01); (FR=1.14, 95% CI: 1.00–1.38; P<0.05) and (FR=1.26, 95% CI: 1.11–1.44; P<0.01); (FR=1.23, 95% CI: 1.08–1.46; P<0.01). Four SNP sites in the nucleotide excision repair (NER) pathway were associated with susceptibility for MN frequency in either unexposed or exposed workers. Further, we observed the gene–MN association changed with exposure for XRCC1 (−77C/T, Arg194Trp, Arg280His, Arg399Gln), XPA Ala23Gly, XPC Ala499Val, XPC Lys939Gln, XPF 5′-UTR T2063A. Moreover, Individuals carrying the XPC (PAT)-(499)-(939) diplotype, PAT-CG/PAT-TG, had a higher MN frequency, compared with individuals carrying the wild-type PAT-CA/PAT-CA.

Associations of Lys939Gln and Ala499Val polymorphisms of theXPCgene with cancer susceptibility: A meta-analysis

XPC polymorphisms may alter DNA repair capacity, thus leading to genetic instability and carcinogenesis. Numerous studies have investigated the associations of XPC Lys939Gln (rs2228001) and Ala499Val (rs2228000) polymorphisms with cancer susceptibility; however, the findings are inconclusive. We searched literature from MEDLINE and EMBASE for eligible publications that assessed the associations between these two polymorphisms and cancer risk. We also assessed genotype-mRNA expression correlation data from HapMap for rs2228001 and rs2228000 in normal cell lines derived from 270 subjects with different ethnicities. The final analysis included 62 published studies of 25,708 cases and 30,432 controls for the Lys939Gln and 34 studies with 14,877 cases and 17,888 controls for the Ala499Val. Overall, Lys939Gln was significantly associated with an increased overall cancer risk (Gln/Gln vs. Lys/Lys: OR = 1.16, 95% CI = 1.07 - 1.25, p < 0.001; recessive model: OR = 1.14, 95% CI = 1.06 - 1.22, p < 0.001; dominant model: OR = 1.06, 95% CI = 1.01 - 1.11, p = 0.015 and Gln vs. Lys: OR = 1.07, 95% CI = 1.03 - 1.10, p < 0.001) and further stratifications showed an increased risk for bladder, lung and colorectal cancer, Asian populations and population-based studies. Likewise, Ala499Val was also significantly associated with an increased overall cancer risk (Val/Val vs. Ala/Ala: OR = 1.21, 95% CI = 1.07 - 1.36, p = 0.003 and recessive model: OR = 1.20, 95% CI = 1.08 - 1.34, p = 0.001) and further stratification showed an increased risk for breast and bladder cancer, particularly in Asian populations. Interestingly, significantly correlation between XPC genotypes and mRNA expression was found only for Asian populations as well. Despite some limitations, this meta-analysis established some solid statistical evidence for an association between XPC polymorphisms and cancer risk, which warrants further validation in single large studies.

DNA Repair Gene Associated with Clinical Outcome of Epithelial Ovarian Cancer Treated with Platinum-based Chemotherapy

The nucleotide excision repair (NER) and base excision repair (BER) pathways, two DNA repair pathways, are related to platinum resistance in cancer treatment. In this paper, we studied the association between single nucleotide polymorphisms (SNPs) of involved genes and response to platinum-based chemotherapy in epithelial ovarian cancer. Eight SNPs in XRCC1 (BER), XPC and XPD (NER) were assessed in 213 patients with epithelial ovarian cancer using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR) techniques. The median progression-free survival (PFS) of patients carrying the Lys/Lys and Lys/Gln+Gln/Gln genotype of the XPC Lys/Gln polymorphism were 25 and 12 months, respectively (P=0.039); and the mean overall survival (OS) of patients was 31.1 and 27.8 months, respectively (P=0.048). Cox's multivariate analysis suggested that patients with epithelial ovarian cancer with the Gln allele had an increased risk of death (HR=1.75; 95% CI=1.06-2.91) compared to those with the Lys/Lys genotype. There are no associations between the XPC PAT+/-, XRCC1 Arg194Trp, Arg280His, Arg399Gln, and XPD Asp312Asn, Lys751Gln polymorphisms and the survival of patients with epithelial ovarian cancer when treated with platinum-based chemotherapy. Our results indicated that the XPC Lys939Gln polymorphism may correlate with clinical outcome of patients with epithelial ovarian cancer when treated with platinum-based chemotherapy in Northern China.

Detection of Polymorphisms of DNA Repair Genes (XRCC1 and XPC) in Prostate Cancer

Prostate cancer is a common disease with a multifactorial and complex etiology. It is the most common male malignancy and the second leading cause of death in many countries. The widespread use of PSA testing has increased the detection of this cancer at earlier stages, although this diagnostic method has proved to be insufficient to identify the disease. DNA in most cells is regularly damaged by endogenous and exogenous mutagens. At least four main partially overlapping damage repair pathways operate in mammals. Common polymorphisms in DNA repair genes may alter protein function and an individual’s capacity to repair damaged DNA; deficits in repair capacity may lead to genetic instability and carcinogenesis. In the present study, we investigated the genotypic distribution of XRCC1 and XPC polymorphisms and its association with prostate cancer risk, pathological staging and Gleason’s scoring. The present study was conducted in the departments of Clinical Pathology, Pathology, and Urology Faculty of Medicine, Alexandria University-Egypt. A total number of 50 patients with pathologically confirmed prostate cancer and 50 age-matched control subjects were enrolled in this study. The diagnosis was made on the basis of histopathological findings, following radical prostatectomy or transurethral resection of the prostate (TURP). Genomic DNA was extracted from peripheral blood using QIAamp blood DNA isolation kits. PCR followed by enzymatic digestion of the PCR products for (XRCC1, XPC) was used for the genotyping of these polymorphisms. Statistical analyses were performed using SPSS statistics version 20. The genotype frequencies of the studied polymorphisms in all the samples (n = 100), PC patients (n = 50) and healthy controls (n = 50) were consistent with the Hardy-Weinberg equilibrium distribution (p-value > 0.05). There was no statistical difference in the genotypes of the XRCC1 Arg399Gln and XPC Lys939Gln between cases and controls. The “Gln” allele frequency of XPC Lys939Gln as well as the “Gln” allele frequency of XRCC1 Arg399Gln tended to be lower in controls than in PC patients. Yet, these decreases were not statistically significant. We also examined the combined effect of XPC and XRCC1 and we found a decreased PC risk when XPC 939 Lys/Lys + Lys/Gln and XRCC1 399 Arg/Arg + Arg/Gln are combined (OR = 0.370, 95% CI = 0.142 - 0.962).

Genetic Polymorphisms in Detoxification and DNA Repair Genes and Susceptibility to Glycidamide-Induced DNA Damage

Acrylamide (AA) is a probable human carcinogen formed in carbohydrate-rich foodstuffs upon heating. Glycidamide (GA), the AA metabolite formed by epoxidation, is considered the ultimate genotoxic agent. In this study, the in vitro genotoxic potential of AA and GA in human whole blood leukocytes was compared using the alkaline comet assay. Although AA did not induce significant DNA damage in the concentrations tested (up to 1000 μM), GA markedly increased the percentage of tail DNA at concentrations ≥250 μM. Further, this study addressed the role of genetic polymorphisms in key genes involved in metabolism and DNA repair pathways (BER, NER, HRR, and NHEJ) on GA-induced genotoxicity assessed by the alkaline comet assay. The results obtained suggested associations between DNA damage and polymorphisms of BER (MUTYH Gln335His and XRCC1 Gln399Arg) and NER (XPC Ala499Val and Lys939Gln) genes, either alone or in combination.