XPC Polymorphisms Research Articles

Nucleotide excision repair gene polymorphisms and hepatoblastoma susceptibility in Eastern Chinese children: A five-center case-control study.

Nucleotide excision repair (NER) plays a vital role in maintaining genome stability, and the effect of NER gene polymorphisms on hepatoblastoma susceptibility is still under investigation. This study aimed to evaluate the relationship between NER gene polymorphisms and the risk of hepatoblastoma in Eastern Chinese Han children. In this five-center case-control study, we enrolled 966 subjects from East China (193 hepatoblastoma patients and 773 healthy controls). The TaqMan method was used to genotype 19 single nucleotide polymorphisms (SNPs) in NER pathway genes, including ERCC1, XPA, XPC, XPD, XPF, and XPG. Then, multivariate logistic regression analysis was performed, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were utilized to assess the strength of associations. Three SNPs were related to hepatoblastoma risk. XPC rs2229090 and XPD rs3810366 significantly contributed to hepatoblastoma risk according to the dominant model (adjusted OR=1.49, 95% CI=1.07-2.08, P=0.019; adjusted OR=1.66, 95% CI=1.12-2.45, P=0.012, respectively). However, XPD rs238406 conferred a significantly decreased risk of hepatoblastoma under the dominant model (adjusted OR=0.68, 95% CI=0.49-0.95; P=0.024). Stratified analysis demonstrated that these significant associations were more prominent in certain subgroups. Moreover, there was evidence of functional implications of these significant SNPs suggested by online expression quantitative trait loci (eQTLs) and splicing quantitative trait loci (sQTLs) analysis. In summary, NER pathway gene polymorphisms (XPC rs2229090, XPD rs3810366, and XPD rs238406) are significantly associated with hepatoblastoma risk, and further research is required to verify these findings.

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.

Genetic Polymorphisms of XPC, XPD, XPG Genes and their Association with Radiotherapy Induced Toxicity among Head and Neck Cancer Patients: A Hospital Based Study from Maharashtra.

The present study was planned to investigate possible association of single nucleotide polymorphisms (SNPs) of nucleotide excision repair (NER) genes such as XPC, XPD, XPG with acute radiation induced toxicities such as skin reactions and oral mucositis in normal tissue from head and neck cancer (HNC) patients receiving radiotherapy. Methods: Two hundred and fifty HNC patients receiving radiotherapy were enrolled in this study and the acute toxicity reactions and radiation response were recorded. Association of SNPs rs2228001 of XPC, rs238406, rs13181 of XPD and rs17655 of XPG gene with normal tissue reactions in the form of dermatitis and mucositis were studied by PCR-RFLP and direct DNA sequencing. The results of univariate analysis of SNPs of XPC, XPD and XPG showed that XPC polymorphism at codon 939 of exon 15 (A>C) was not associated with dermatitis (OR=0.30, 95% CI: 0.06-1.39; p=0.125), or oral mucositis (OR=1.14, 95% CI: 0.41-3.20; p=0.793). The XPD codon 156 of exon 6 (C>A) and codon 751 of exon-23 A>C) polymorphism showed no association with radiosensitivity in HNC patients (OR=1.50, 95% CI: 0.60-3.71; p=0.080) for dermatitis, (OR=1.54, 95% CI: 0.66-3.61; p=0.312) for oral mucositis. The 1104 Asp variant genotype or allele of XPG (OR=1.35 95% CI: 0.50-3.64; p=0.541) showed no association with degree of radiotherapy associated dermatitis or mucositis (OR=0.80, 95% CI: 0.32-2.03; p=0.648) in HNC patients. The variant C allele of 2920 A/C genotype of XPC gene at codon 939 of exon 15, found protective with developing skin reactions with grade >1 (OR=0.60, 95% CI: 0.36-0.97; p=0.039) in HNC patients treated with radiotherapy. The results obtained in this study concluded that the SNPs rs2228001of XPC, rs238406, rs13181 SNPs of XPD and rs17655 SNP of XPG are not associated with normal tissue toxicity in HNC patients treated with radiotherapy. Radiotherapy with high radiation dose was significantly associated with oral mucositis in response to radiotherapy.

Impact of DNA repair polymorphisms on DNA instability biomarkers induced by lead (Pb) in workers exposed to the metal

Although the mechanisms of Pb-induced genotoxicity are well established, a wide individual's variation response is seen in biomarkers related to Pb toxicity, despite similar levels of metal exposure. This may be related to intrinsic variations, such as genetic polymorphisms; moreover, very little is known about the impact of genetic variations related to DNA repair system on DNA instability induced by Pb. In this context, the present study aimed to assess the impact of SNPs in enzymes related to DNA repair system on biomarkers related to acute toxicity and DNA damage induced by Pb exposure, in individuals occupationally exposed to the metal. A cross-sectional study was run with 154 adults (males, >18 years) from an automotive batteries' factory, in Brazil. Blood lead levels (BLL) were determined by ICP-MS; biomarkers related to acute toxicity and DNA instability were monitored by the buccal micronucleus cytome (BMNCyt) assay and genotyping of polymorphisms of MLH1 (rs1799977), OGG1 (rs1052133), PARP1 (rs1136410), XPA (rs1800975), XPC (rs2228000) and XRCC1 (rs25487) were performed by TaqMan assays. BLL ranged from 2.0 to 51 μg dL−1 (mean 20 ± 12 μg dL−1) and significant associations between BLL and BMNCyt biomarkers related to cellular proliferation and cytokinetic, cell death and DNA damage were observed. Furthermore, SNPs from the OGG1,XPA and XPC genes were able to modulate interactions in nuclear bud formation (NBUDs) and micronucleus (MNi) events. Taken together, our data provide further evidence that polymorphisms related to DNA repair pathways may modulate Pb-induced DNA damage; studies that investigate the association between injuries to genetic material and susceptibilities in the workplace can provide additional information on the etiology of diseases and the determination of environmentally responsive genes.

Association of Single-Nucleotide Polymorphisms of Gene XPC with Susceptibility to Basal Cell Carcinoma in Brazilian Population

Background: Basal cell carcinoma (BCC) is the common neoplasm in humans and its main etiological factor is exposure to solar radiation. Mutations in repair genes can lead to tumor progression and loss of cell integrity leading to the onset of cancer. Nucleotide excision repair (NER) is an important mechanism primarily used to repair injuries caused by UV. Objective: To evaluate and describe for the first time the single nucleotide polymorphisms rs745769173, rs761106780 and rs535425175 and risk of developing BCC. Methods: The present study analyzed 100 samples of paraffin-embedded tissue from patients with histopathological diagnosis of BCC and 100 control samples. The results were obtained by genotyping method, Dideoxy Unique Allele Specific – PCR (DSASP) and molecular modeling. Results: The SNP rs535425175 of the XPC gene showed a significant association with the BCC in the analyzed samples (P &lt;0.005) and molecular docking showed different binding energy of the complex between the XPC region 99-156 and the PH domain of TFIIH p62, being more negative, -710.53 kcal/mol, with the Asn residue at position 108 and less negative, -611.10 kcal/mol, with Lys residue related to the polymorphism. Conclusion: The results suggest that the SNP rs535425175 of the XPC gene, which causes mutation at codon 108 of the XPC protein, which consists of replacing the Ans residue with the Lys, may be considered a risk factor associated with the development of BCC.

Joint effects of polycyclic aromatic hydrocarbons, smoking, and XPC polymorphisms on damage in exon 2 of KRAS gene among young coke oven workers.

Genetic polymorphisms may contribute to individual susceptibility to DNA damage induced by environmental exposure. In this study, we evaluate the effects of co-exposure to PAHs, smoking and XPC polymorphisms, alone or combined, on damage in exons. A total of 288 healthy male coke oven workers were enrolled into this study, and urinary 1-hydroxypyrene (1-OH-Pyr) was detected. Base modification in exons of KRAS and BRAF gene, and polymorphisms of XPC were determined in plasma by real-time PCR. We observed 1-OH-Pyr was positively related to damage in exon 2 of KRAS (KRAS-2) and in exon 15 of BRAF (BRAF-15), respectively, and KRAS-2 and BRAF-15 were significantly associated with increased 1-OH-Pyr. A stratified analysis found 1-OH-Pyr was significantly associated with KRAS-2 in both smokers and non-smokers, while 1-OH-Pyr was significantly associated with BRAF-15 only in smokers. Additionally, individuals carrying both rs2228001 G-allele (GG+GT) and rs3731055 GG homozygote (GG) genotype appeared to have more significant effect on KRAS-2. The high levels of 1-OH-Pyr were associated with KRAS-2 only in rs2228001 GG+GT genotype carriers and the high levels of 1-OH-Pyr were associated with KRAS-2 only in rs3731055 GG genotype carriers and the most severe KRAS-2 was observed among subjects carrying all four of the above risk factors. Our findings indicated the co-exposure effect of PAHs and smoking could increase the risk of KRAS-2 by a mechanism partly involving XPC polymorphisms.

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.

Genetic polymorphisms of GSTP1, XRCC1, XPC and ERCC1: prediction of clinical outcome of platinum-based chemotherapy in advanced non-small cell lung cancer patients of Bangladesh.

Inter-individual genetic makeup can trigger variability in platinum-based chemotherapeutic responses and corresponding adverse drug reactions and toxicities. Exploring the genetic causes behind these inter-individual variabilities in platinum-based chemotherapeutic responses by investigating the effects of GSTP1 (rs1695), XRCC1 (rs25487), XPC (rs2228001) and ERCC1 (rs11615) genetic polymorphisms on toxicity and therapeutic response of this treatment among Bangladeshi advanced non-small cell lung cancer (NSCLC) patients was the aim of this study. 285 Clinically proven either stage IIIB or IV (advanced) NSCLC patients aging not less than 18years old and receiving platinum-based chemotherapy were recruited to assess the influence of these four single nucleotide polymorphisms (SNPs) on peripheral leukocytes. Toxicity and response were evaluated by multivariate regression analyses using SPSS statistical software (version 17.0). XRCC1 (rs25487) polymorphism was found to act as a predictive factor for not only grade 3 and 4 anemia (p = 0.008), neutropenia (p = 0.010), thrombocytopenia (p = 0.025) and gastrointestinal toxicity (p = 0.002) but also for therapeutic response (p = 0.012) in platinum-based chemotherapy. Although GSTP1 (rs1695) polymorphism might serve as prognostic factor regarding grade 3 or 4 neutropenia, a significant (p = 0.044) improvement in response to platinum-based chemotherapy was observed. However, XPC (rs2228001) and ERCC1 (rs11615) polymorphisms could not establish any significant relation with toxicity or therapeutic response. XRCC1 (rs2228001) and GSTP1 (rs1695) polymorphisms might explain platinum-induced clinical outcomes in terms of both toxicity and therapeutic response variations among Bangladeshi advanced NSCLC patients.

The Relationship of XPA and XPC Gene Polymorphisms with the Risk of Colorectal Cancer in Iran

Background: The objective of this study was to investigate the effect of several XPA and XPC polymorphisms on the risk of colorectal cancer (CRC) in northeastern Iran. Method: 180 CRC patients and 160 healthy subjects participated in this case-control study. We determined the genotypes by RFLP-PCR and PIRA-PCR, and analyzed the results using logistic regression and ᵡ2-test. Result: Our findings showed that only BMI could affect the risk of cancer among the studied demographic factors. Three of the four polymorphisms studied, namely XPA A23G, XPC rs2228000 C > T and XPC rs2228001 A > C, did not correlate with CRC (P-values > 0.05); however, the polymorphism of XPC poly AT (PAT) increased the risk of CRC (P= 0.024). The XPC rs2228000 C> T polymorphism increased the CRC risk only in patients aged 50 or more. The risk of CRC in heterozygote individuals (XPC PAT D/I) was higher than that of homozygous individuals (XPC PAT D/D); also, at least one PAT I variant allele increased the likelihood of CRC (for PAT D/I OR =2.168; 95% CI = 1.809-4.319: and for PAT D/I and PAT I/I OR = 1.810; 95% CI = 1.165-2.813). The XPC haplotypes were similar between the cases and controls, and P-values were >0.05. Conclusion: In the whole population, XPC PAT polymorphism, overweightness, and XPC rs2228000 C>T polymorphism in elderly people are related to CRC. Therefore, they can probably be considered as markers of CRC in Iran.

XPC as breast cancer susceptibility gene: evidence from genetic profiling, statistical inferences and protein structural analysis.

Gene polymorphisms that affect nucleotide excision repair (NER) pathway may link with higher susceptibility of breast cancer (BC); however, the significance of these associations may vary conferring to the individual ethnicity. Xeroderma pigmentosum complementation gene (XPC) plays a substantial role in recognizing damaged DNA during NER process. To estimate the relationship among XPC polymorphisms and breast cancer (BC) risk, we carried out a case-control-association study with 493 BC cases and 387 controls using TETRA-ARMS-PCR. Distributional differences of clinical features, demographic factors and XPC polymorphisms among BC cases and controls were examined by conditional logistic regression model. Kaplan-Meier test was applied to predict survival distributions and protein structure was predicted using computational tools. Obesity, consanguinity, positive marital status and BC family history were associated (P ≤ 0.01) with higher BC risk. Genotyping revealed significant involvement (P ≤ 0.01) of two XPC polymorphisms rs2228001-A > C (OR = 3.8; CI 1.9-7.6) and rs2733532-C > T (OR = 2.6; CI 1.4-5.03) in BC development, asserting them potential risk factors for increased BC incidence. However, no association (P > 0.05) was detected for overall or progression free survival for both XPC polymorphisms possibly due to shorter follow-up time (45months). As compared to normal XPC structure, pronounced conformational changes have been observed in the C-terminus of XPCQ939K, bearing rs2228001-A > C substitution. In XPCQ939K, two additional α-helices were observed at A292-E297 and Y252-R286, while L623-M630 and L649-L653 helices were converted into loop conformation. In conclusion, both XPC polymorphisms confer significant association with increased BC risk. rs2228001 substitution may change the structural and functional preferences of XPC C-terminus, while rs2733532 may have regulatory role thereby leading to potential BC risk.

Lack of association between three common genetic variations of XPC and susceptibility to age-related macular degeneration, a preliminary study

BackgroundNumerous association studies have indicated that genetic alterations in genes involved in DNA repair processes are associated with the risk of age-related macular degeneration (ARMD). There is no published study on the relationship between common xeroderma pigmentosum complementation group C (XPC, MIM 613208) polymorphisms and susceptibility to ARMD. The aim of this study is to determine whether three common (Ala499Val, Lys939Gln, and PAT) genetic variants of XPC are associated with the risk of developing ARMD. A total of 120 ARMD patients and 118 healthy controls were included in the study. Genotyping analyses were carried out by PCR-based methods.ResultsOur analysis revealed that there was no relationship between the XPC polymorphisms and susceptibility to ARMD. In both case and control groups, strong linkage disequilibrium existed between three common (Ala499Val, Lys939Gln, and PAT) genetic polymorphisms of XPC. Statistical analysis showed no association between the haplotypes and the risk of ARMD.ConclusionsThe present data indicated that the common polymorphisms of XPC are not susceptible genetic variations for ARMD.

Variants in XPC, Noxa and TLR4 genes are not associated with bleomycin-induced lung injury in Hodgkin lymphoma patients.

Aim: Pulmonary toxicity is a well-known adverse reaction of bleomycin. In this study, we investigated the influence of XPC, PMAIP1/Noxa and TLR4 genetic variants on the development of bleomycin-induced lung injury (BILI) in south Indian patients with Hodgkin lymphoma. Materials & methods: Hodgkin lymphoma patients receiving adriamycin, bleomycin, vinblastine and dacarbazine regimen were recruited for the study and BILI was diagnosed based on symptoms and/or radiological signs. DNA samples were genotyped using real-time PCR. Results: A total of 78 patients were recruited in the study and BILI was observed in 17 (21.8%) patients. Polymorphisms in XPC, PMAIP1/Noxa and TLR4 genes were not associated with the development of BILI. Conclusion: The selected genetic polymorphisms do not predict the risk of BILI in south Indian population.

Smoking and XPC Gene Polymorphism Interact to Modulate the Risk of Oral Cancer.

Oral cancer is the most common cancer among the Indian men and the second most common cancer among the Indian women. Such high incidence of oral cancer in India is due to consumption of tobacco in different form including smoking of cigarette. Smoke of tobacco contains different carcinogens which causes DNA damage. Such DNA damage if remain unrepaired due to faulty DNA repair system can cause mutation and eventual development of cancer. In the present study, we aimed to check the role of smoking as well as interaction of smoking and XPC polymorphism in risk modulation of oral cancer. Total of 372 subjects including 300 healthy controls and 72 patients of oral cancers been genotyped for the XPC PAT D/I, A/C and C/T polymorphisms with PCR based or PCR-RFLP based method. Genotype frequency was analyzed by chi-square test and strength of associations by odds ratio with 95% confidence intervals. The present study showed that compared to nonsmokers, smokers are at five times higher risk to develop oral cancer (p value= 0.001, OR= 5.03, 95% CI 2.91-8.69) and three times higher risk to develop node-positive (p value= 0.01, OR= 3.66, 95% CI 1.34-9.95) oral cancer. It has also been observed that individuals who were smokers and carrier of variant allele genotypes (AC and CC) for XPC A/C polymorphism were at threefold higher risk (p value= 0.01, OR=2.97, 95% CI 1.29-6.86) to develop oral cancer compared to individual who were smokers but do not carry the C allele (AA genotype). This observation indicates that C allele of XPC A/C polymorphism interacts with smoking and significantly increases the risk of oral cancer. This study demonstrates a possible role of smoking and gene-smoking interaction in risk enhancement of oral cancer.

Clinical Significance of ERCC2, XPC, ERCC5 and XRCC3 Gene Polymorphisms in Diffuse Large B Cell Lymphoma

Clinical Significance of ERCC2, XPC, ERCC5 and XRCC3 Gene Polymorphisms in Diffuse Large B Cell Lymphoma

Noninvasive circulating tumor cell and urine cellular XPC (rs2228001, A2815C) and XRCC1 (rs25487, G1196A) polymorphism detection as an effective screening panel for genitourinary system cancers.

BackgroundValid cancer screening and treatment monitoring are critical for cancer patients. Although genitourinary system cancers have a high recurrence rate, when diagnosed, patients undergo surgery promptly. We sought to explore sensitive and noninvasive screening and postoperative recurrence monitoring methods, such as circulating tumor cells (CTCs) or tumor susceptibility gene detection, to determine their appropriateness for genitourinary system cancers.MethodsWe adopted multiple detection methods. Enrichment-immunofluorescence in situ hybridization (SE-iFISH) was employed to detect CTCs from the peripheral blood of patients, and Agena Bioscience MassARRAY was used to detect single-nucleotide polymorphisms (SNPs) in tumor susceptibility genes from urine cells.ResultsIn our research, CTCs showed a 76.92% positivity rate among 26 genitourinary system cancer patients, and the number of CTCs was consistent with the stage of cancer. In monitoring for bladder cancer (BC) recurrence, CTCs were more prevalent than urine cytology (66.67% vs. 41.67%). To our surprise, urine cellular XPC (rs2228001, A2815C) and XRCC1 (rs25487, G1196A) polymorphisms were specifically found in cancer patients but not in patients with inflammation or in healthy individuals. XPC polymorphism (rs2228001, A2815C) rates were 30.77%, 40%, and 50% in bladder cancer, renal carcinoma, and prostate cancer patients, respectively, and those for XRCC1 (rs25487, G1196A) were 3.85%, 20%, and 25%, respectively.ConclusionsAs a common biomarker, CTCs showed remarkable performance in cancer screening and monitoring. The noninvasive panel comprising CTCs and XPC (rs2228001, A2815C) and XRCC1 (rs25487, G1196A) polymorphisms showed high sensitivity (positive rate: 92.86%) and is suitable for genitourinary system cancer screening.

Association between three common genetic polymorphisms of XPC and susceptibility to heroin dependency

As heroin and morphine produce reactive oxygen species and down-regulate several genes involved in cellular detoxification and DNA repair pathways, neurons experience DNA damage. Xeroderma pigmentosum complementation group C (XPC, OMIM: 613208) gene, which is expressed in the brain, is one of the central genes in the nucleotide excision repair pathway. Three common XPC polymorphisms (Lys939Gln, Ala499Val and PAT) are associated with reduced DNA repair capacity. In this study, the relationship between these polymorphisms and the risk of heroin dependency (HD), as well as, age of first use (AFU) for illegal drugs was investigated on 795 healthy individuals and 442 heroin dependent patients. Statistical analyses indicated that there was no significant association between the XPC polymorphisms and the risk of HD. The haplotypic frequencies of the polymorphisms showed significant difference between HD patients and healthy controls (χ2 = 16.38, df = 6, P = 0.012). Analysis indicated that the “Ala + Gln” haplotype increased the HD risk more than the “Ala + Lys” haplotype (OR = 4.21, 95% CI = 1.29–13.7, P = 0.017). In Cox proportional model, there was significant association between AFU and the Ala499Val polymorphism (Hazard ratio = 1.53, 95% CI: 1.02–2.92, P = 0.036). To investigate the effect of the linkage between the polymorphic sites, we compared the AFU among two common diplotypes (“Ala − Lys/Ala − Lys” and “Val − Lys/Val − Lys”). Statistical analysis indicated that AFU was significantly lower in “Val − Lys/Val − Lys” diplotype (t = 2.63, df = 49, P = 0.011). The present findings suggest that the XPC is a candidate polymorphic locus for AFU.

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.

The fine art of vascular wall maintenance. Carriership of XPC, TP53 and APOE polymorphisms may be a risk factor for cerebral vascular accidents in the Bulgarian population

Efficient maintenance of the integrity of the endothelium of cerebral blood vessels is crucially important, especially when the vessel walls are subjected to greater-than-normal levels of stress. Persistently high levels of genotoxic stress may result from lower capacity to detect and repair DNA damage conferred by carriership of variants of key genes of DNA repair/maintenance of genomic integrity. Adult Bulgarian patients with a history of cerebral vascular accidents (CVAs) and age-matched healthy controls were analyzed for 11 markers, including 7 DNA polymorphisms in genes coding for proteins of DNA repair and maintenance of genomic integrity, 3 hypercoagulability markers and 1 marker for susceptibility for cerebral amyloidosis. Homozygous carriership of the del allele of the polymorphism XPCins83 was associated with decreased risk of CVAs (RR = 0.446, 95% CI:0.225–0.886, p = 0.021). In individuals carrying the 'protective' del/del XPCins83 genotype, carriership of the 'pro-apoptotic' genotype Arg/Arg in the TP53 locus was associated with increased risk of CVAs (RR = 1.845, 95% CI:1.049–3.244, p = 0.034). Carriers of the Lys751Gln genotype at the ERCC2 locus were at increased risk of CVAs (RR = 2.055, 95% CI:1.09–3.876, p = 0.025). Carriership of the E2/E3 genotype at the APOE locus decreased the risk of CVAs in Bulgarian males (RR = 0.279, 95% CI:0.090–0.873, p = 0.028). Male Bulgarian carriers of the APOE4 allele were at increased risk of CVAs. Carriership of the common prothrombotic mutations Factor V Leiden, PT G20210A, MTHFR C677T and PAI1 4G/5G had no significant effect on the risk of CVAs in Bulgarian adults.

Predictive Value of Single Nucleotide Polymorphisms of ERCC1, XPA, XPC, XPD and XPG Genes, Involved in NER Mechanism in Patients with Advanced NSCLC Treated with Cisplatin and Gemcitabine

The combination of cisplatin and gemcitabine is still one of the most frequently used first-line chemotherapy scheme in patients with advanced non-small cell lung cancer (NSCLC), in which tyrosine kinase inhibitors (TKIs) cannot be administered. Unfortunately, more than half of the patients have no benefit from chemotherapy but are still exposed to its toxic effects. Therefore, single nucleotide polymorphisms (SNPs) in the genes involved in nucleotide excision repair (NER) mechanism may be a potential predictive factor of efficiency of cytostatic based chemotherapy. The aim of the study was to evaluate the correlation between SNPs of the genes involved in NER mechanism and the effectiveness of chemotherapy based on cisplatin and gemcitabine in patients with advanced NSCLC. The study group included 91 NSCLC patients treated with first-line chemotherapy using cisplatin and gemcitabine. Genotyping was carried out using a mini-sequencing technique (SNaPshot™ PCR). The median progression-free survival (PFS) was significantly shorter in carriers of CC genotype of the XPD/ERCC2 (2251A > C) gene compared to patients with AA/AC genotypes (2 vs. 4.5 months; p = 0.0444; HR = 3.19, 95%CI:1.03–9.91). Rare CC genotype of XPD/ERCC2 gene, may be considered as an unfavorable predictive factor for chemotherapy based on cisplatin and gemcitabine in patients with advanced NSCLC.

Exposure to meat-derived carcinogens and bulky DNA adduct levels in normal-appearing colon mucosa

IntroductionMeat consumption is a risk factor for colorectal cancer. This research investigated the relationship between meat-derived carcinogen exposure and bulky DNA adduct levels, a biomarker of DNA damage, in colon mucosa. MethodsLeast squares regression was used to examine the relationship between meat-derived carcinogen exposure (PhIP and meat mutagenicity) and bulky DNA adduct levels in normal-appearing colon tissue measured using 32P-postlabelling among 202 patients undergoing a screening colonoscopy. Gene-diet interactions between carcinogen exposure and genetic factors relevant to biotransformation and DNA repair were also examined. Genotyping was conducting using the MassARRAY® iPLEX® Gold SNP Genotyping assay. ResultsPhIP and higher meat mutagenicity exposures were not associated with levels of bulky DNA adducts in colon mucosa. The XPC polymorphism (rs2228001) was found to associate with bulky DNA adduct levels, whereby genotypes conferring lower DNA repair activity were associated with higher DNA adduct levels than the normal activity genotype. Among individuals with genotypes associated with lower DNA repair (XPD, rs13181 and rs1799179) or detoxification activity (GSTP1, rs1695), higher PhIP or meat mutagenicity exposures were associated with higher DNA adduct levels. Significant interactions between the XPC polymorphism (rs2228000) and both dietary PhIP and meat mutagenicity on DNA adduct levels was observed, but associations were inconsistent with the a priori hypothesized direction of effect. ConclusionExposure to meat-derived carcinogens may be associated with increased DNA damage occurring directly in the colon among genetically susceptible individuals.