DNA Repair Gene XPD Research Articles

Поліморфізм генів репарації ДНК XRCC1 та XPD у хворих на рак щитоподібної залози, які зазнали дії іонізуючої радіації внаслідок аварії на Чорнобильській АЕС

Поліморфізм генів репарації ДНК XRCC1 та XPD у хворих на рак щитоподібної залози, які зазнали дії іонізуючої радіації внаслідок аварії на Чорнобильській АЕС

Impact of polymorphisms in DNA repair genes XPD, hOGG1 and XRCC4 on colorectal cancer risk in a Chinese Han Population.

Background: This research aimed to study the associations between XPD (G751A, rs13181), hOGG1 (C326G, rs1052133) and XRCC4 (G1394T, rs6869366) gene polymorphisms and the risk of colorectal cancer (CRC) in a Chinese Han population. Method: A total of 225 Chinese Han patients with CRC were selected as the study group, and 200 healthy subjects were recruited as the control group. The polymorphisms of XPD G751A, hOGG1 C326G and XRCC4 G1394T loci were detected by the RFLP-PCR technique in the peripheral blood of all subjects. Results: Compared with individuals carrying the XPD751 GG allele, the A allele carriers (GA/AA) had a significantly increased risk of CRC (adjusted OR = 2.109, 95%CI = 1.352–3.287, P=0.003). Similarly, the G allele (CG/GG) of hOGG1 C326G locus conferred increased susceptibility to CRC (adjusted OR = 2.654, 95%CI = 1.915–3.685, P<0.001). In addition, the T allele carriers (GT/TT) of the XRCC4 G1394T locus have an increased risk of developing CRC (adjusted OR = 4.512, 95%CI = 2.785–7.402, P<0.001). The risk of CRC was significantly increased in individuals with both the XPD locus A allele and the hOGG1 locus G allele (adjusted OR = 1.543, 95%CI = 1.302–2.542, P=0.002). Furthermore, individuals with both the hOGG1 locus G allele and the XRCC4 locus T allele were predisposed to CRC development (adjusted OR = 3.854, 95%CI = 1.924–7.123, P<0.001). The risks of CRC in XPD gene A allele carriers (GA/AA) (adjusted OR = 1.570, 95%CI = 1.201–1.976, P=0.001), hOGG1 gene G allele carriers (CG/GG) (adjusted OR = 3.031, 95%CI = 2.184–4.225, P<0.001) and XRCC4 gene T allele carriers (GT/TT) (adjusted OR = 2.793, 95%CI = 2.235–3.222, P<0.001) were significantly higher in patients who smoked ≥16 packs/year. Conclusion: Our results suggest that XPD G751A, hOGG1 C326G and XRCC4 G1394T gene polymorphisms might play an important role in colorectal carcinogenesis and increase the risk of developing CRC in the Chinese Han population. The interaction between smoking and these gene polymorphisms would increase the risk of CRC.

DNA Repair Gene (XPD, XRCC4, and XRCC1) Polymorphisms in Patients with Endometrial Hyperplasia: A Pilot Study.

BackgroundIn this study, we aimed to evaluate the association between endometrial hyperplasia and DNA repair gene (XPD, XRCC4, and XRCC1) polymorphisms.Material/MethodsThere were 114 cases enrolled in the study in 4 groups: simple endometrial hyperplasia (SH) (Group 1), complex endometrial hyperplasia without atypia (CH) (Group 2), complex atypical endometrial hyperplasia (CAH) (Group 3), and normal endometrium (NE) (Group 4). Of these cases, 37 cases had SH, 36 cases had CH, 16 cases had CAH, and 25 cases had NE. To evaluate an association between atypia and DNA repair genes, we consider a group that included both SH and CH, the endometrial hyperplasia without atypia cases (Group 5). Genomic DNA was isolated from paraffin-embedded endometrial tissue collected from the Pathology Department of Gaziantep University Medical School. Polymerase chain reaction (PCR) and/or restriction fragment length polymorphism (RFLP) method was used for evaluating of XPD (−751), XRCC4 (−1394 and a variable number of tandem repeats in intron 3), and XRCC1 (−399) genes.ResultsWe observed a notable distinction in patients having endometrial hyperplasia without atypia (the SH+CH group) and the CAH group in terms of XPD (−751) gene polymorphisms. A notable contrast was observed in patients with endometrial hyperplasia without atypia (the SH+CH group) and the NE group in terms of XRCC4 (VNTR intron 3) polymorphisms (P=0.026, P=0.018, respectively).ConclusionsIt was evident the DNA repair gene XPD and XRCC4 polymorphisms had a role in the pathophysiology of endometrial hyperplasia.

DNA Repair Gene XRCC1 and XPD Polymorphisms and Gastric Cancer Risk: A Case-Control Study Outcome from Kashmir, India.

Coding polymorphisms in several DNA repair genes have been reported to affect the DNA repair capacity and are associated with genetic susceptibility to many human cancers, including gastric cancer. An understanding of these DNA repair gene polymorphisms might assess not only the risk of humans exposed to environmental carcinogens but also their responses to different therapeutical approaches, which target the DNA repair pathway. In the present study, polymorphic variants of two DNA repair genes, XRCC1 Arg399Gln and XPD Lys751Gln, were chosen to be studied in association with gastric cancer susceptibility in the Kashmiri population. A total of 180 confirmed cases of gastric cancer (GC) and 200 hospital-based controls from Government Shri Maharaja Hari Singh Hospital, Srinagar, were included in the study. The genotyping for XRCC1 and XPD genes was carried out by polymerase chain reaction-restriction fragment length polymorphism. We found that tobacco smoking is strongly associated with GC risk (OR = 25.65; 95% CI: 5.49–119.7). However, we did not find any association of polymorphism of XRCC1 Arg399Gln (OR = 1.56; 95% CI: 0.32–7.82) and XPD Lys751Gln (OR = 0.46; CI: 0.10–2.19) with GC risk in the study population. The combination of genotypes and gender stratification of XRCC1 and XPD genotypic frequency did not change the results. Consumption of large volumes of salt tea was also not associated with gastric cancer risk. Polymorphic variants of XRCC1 Arg399Gln and XPD Lys751Gln are not associated with the risk of gastric cancer in the Kashmiri population. However, replicative studies with larger sample size are needed to substantiate the findings.

Lead Induces Genotoxicity via Oxidative Stress and Promoter Methylation of DNA Repair Genes in Human Lymphoblastoid TK6 Cells.

BackgroundLead (Pb) is a widely used metal in modern industry and is regarded as a health hazard. Although lead-induced genotoxicity has been confirmed, the direct evidence that lead induces genotoxicity in human cells and its related mechanisms has not been fully elucidated. In this study, for the first time, we evaluated the genotoxicity induced by lead in human lymphoblastoid TK6 cells.Material/MethodsThe TK6 cells were incubated with various concentrations of Pb(Ac)2 for 6 h, 12 h, or 24 h. Cell viability was detected by CCK8 assay. Various biochemical markers were assessed by specific kits. Immunofluorescence assay was used to detect γ-H2AX foci formation. The promoter methylation was assessed by methylation-specific PCR. The protein levels were determined by Western blot assay.ResultsThe results showed that after exposure to lead, cell viability was obviously decreased and γ-H2AX foci formation was significantly enhanced in TK6 cells. Moreover, the levels of 8-OHdG, ROS, MDA, and GSSG were increased, while the GSH level and SOD activity were decreased in lead-treated TK6 cells. The activation of the Nrf2-ARE signaling pathway was involved in lead-induced oxidative stress in TK6 cells. Finally, the expressions of DNA repair genes XRCC1, hOGG-1, BRCA1, and XPD were inhibited via enhancing their promoter methylation in TK6 cells after exposure to lead.ConclusionsTaken together, our study provides the first published evidence that lead exposure results in DNA damage via promoting oxidative stress and the promoter methylation of DNA repair genes in human lymphoblastoid TK6 cells.

Impact of DNA Repair Genes Polymorphisms on Incidence and Prognosis of Breast Cancer in an Egyptian Cohort

Background: Sporadic breast cancer might be caused by low-penetrance genes, including genes constituting the DNA repair pathways. Defective DNA repair is a common imprint of cancer that promotes the accretion of DNA errors and genomic instability. The clustering of damage in DNA may stimulate breast carcinogenesis. Aims: The goal of the study is to evaluate the role of single nucleotide polymorphisms in DNA repair genes XRCC1 Arg399Gln, XPD Lys751Gln, RAD51 G135C and XRCC3 Thr241Met as genetic indicators of susceptibility to breast cancer and to evaluate their role in treatment outcome. Methodology: The study included 248 females diagnosed with primary breast cancer and 232 normal healthy females. Patients were clinically followed up for 5 years after completing chemotherapy. Genomic DNA was isolated and the four polymorphisms under investigation were assessed by PCR-RFLP technique. Findings: XRCC1 399Gln, XPD 751Gln and XRCC3 241Met alleles were significantly associated with breast cancer risk (OR = 2.63, 2.17 and 3.21; respectively), with carriers having lower disease free survival (DSF). When grouping patients based on the number of affected genotypes they carry, DFS decreased as the number of affected genotypes increased (PaccumConclusion: XRCC1 Arg399Gln, XPD Lys751Gln and XRCC3 Thr241Met polymorphisms may take a significant part in sporadic breast cancer as risk factors and in prognosis, where patients carrying XRCC1 Arg/Arg, XPD Lys/Lys and XRCC3 Thr/Thr genotypes had significantly diminished risk for breast cancer and higher DFS. DFS decreased as the number of affected genotypes increased. But RAD51 5'UTR G135C polymorphism did not associate with either risk or prognosis of breast cancer.

POLYMORPHISM OF DNA REPAIR GENE XPD Lys751Gln AND CHROMOSOME ABERRATIONS IN LYMPHOCYTES OF THYROID CANCER PATIENTS EXPOSED TO IONIZING RADIATION DUE TO THE CHORNOBYL ACCIDENT

XPD Lys751Gln polymorphisms were detected by polymerase chain reaction in 102 TC patients including 38 patients exposed to ionizing radiation due to Chornobyl disaster (Chornobyl recovery workers, evacuees, and the residents of contaminated areas), 64 patients without history of ionizing radiation exposure and 45 healthy residents of Ukraine as control group. In homozygous carriers of the minor allele XPD Gln751Gln, exposed to ionizing radiation, the significantly increased risk of TC (odds ratio = 3.66; p = 0.03; 95% confidence interval 1.04-12.84) was found. Among evacuees and residents of contaminated areas, homozygous carriers of the minor allele variants of XPD gene were characterized by the high level of spontaneous chromosome aberrations. TC patients without history of ionizing radiation exposure, being homozygous carriers of the allele XPD Lys751Lys, had significantly reduced frequency of chromosome-type aberrations. The carriage of homozygous minor allele of DNA repair gene XPD Gln751Gln is a risk factor for TC in persons from Ukrainian population exposed to ionizing radiation and is associated with the increased levels of chromosomal instability. This article is a part of a Special Issue entitled "The Chornobyl Nuclear Accident: Thirty Years After".

DNA repair genes XPC, XPD, XRCC1, and XRCC3 are associated with risk and survival of squamous cell carcinoma of the head and neck.

Head and neck squamous cell carcinomas (HNSCC) are a heterogenous group of tumors with a high rate of early recurrences, second primary tumors, and mortality. Despite advances in diagnosis and treatment over the past decades, the overall 5-year survival rate remains around 50%. Since the head-and neck-region is continuously exposed to potentially DNA-damaging exogenous and endogenous factors, it is reasonable to expect that the DNA repair genes play a part in the development, progression, and outcome of HNSCC. The aim of this study was to investigate the SNPs XPC A499V, XPD K751Q, XRCC1 R399Q, and XRCC3 T241M as potential risk factors and indicators of survival among Caucasian patients. One-hundred-sixty-nine patients as well as 344 healthy controls were included and genotyped with PCR-RFLP. We showed that XPC A499V was associated with increased risk of HNSCC, especially laryngeal carcinoma. Among women, XPD K751Q was associated with increased risk of oral SCC. Furthermore, XPD homozygous mutant individuals had the shortest survival time, a survival time that increased however after full dose radiotherapy. Wild-type individuals of XRCC3 T241M demonstrated an earlier age of onset. HPV-positive never smokers had lower frequencies of p53 mutation. Among HNSCC patients, HPV-positivity was significantly associated with XRCC1 R399Q homozygous mutant genotype. Moreover, combinations of putative risk alleles seemed to act synergistically, increasing the risk of HNSCC. In conclusion, our results suggest that SNPs of the DNA repair genes XPC, XPD, XRCC1, and XRCC3 may affect risk and survival of HNSCC.

Research of DNA repair genes polymorphism XRCC1 and XPD and the risks of thyroid cancer development in persons exposed to ionizing radiation after Chornobyl disaster

The objective of this work was to determine and compare the features of DNA repair gene XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms in patients with thyroid cancer (TC), who were exposed to ionizing radiation (IR) as a result of the Chornobyl disaster, and in patients without exposure to ionizing radiation in history. Determination of gene XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms was performed by polymerase chain reaction (PCR) in 102 patients with thyroid cancer: 38 people, who were exposed to ionizing radiation due to Chornobyl disaster (members of the accident, and evacuees and residents from controlled areas contaminated with radionuclides), 64 individuals without exposure to ionizing radiation in history and 41 persons residents of Ukraine without cancer pathology in the control group. For comparison of the data on spontaneous and radiation-associated thyroid cancer and settlement of allele frequencies differences and risk of cancer pathology were used the literature data on control groups of populations of Russia, Belarus and Poland. Comparing to the literature data on XRCC1 Arg399Gln polymorphisms in radiation-exposed individuals without cancer pathology, the risk of thyroid cancer in homozygous minor allele XRCC1 Gln399Gln carriers, who were exposed to ionizing radiation was significantly increased: OR = 4,14, p = 0,001 (CI95 % 1,72-9,93). In homozygous carriers of the minor allele of the gene XPD Lys751Gln, exposed to IR, revealed increased risk of thyroid cancer: OR = 3,30, p = 0,05 (CI 95 % 0,82-14,14), when compared with the control group of Ukrainian population. The carriage of homozygous minor allele Gln399Gln XRCC1 and XPD Gln751Gln of DNA repair genes is a risk factor for thyroid cancer under the influence of ionizing radiation in research group of Ukrainian population.

Polymorphism of DNA repair genes OGG1, XRCC1, XPD and ERCC6 in bladder cancer in Belarus

Context: The study of DNA base and nucleotide excision repair gene polymorphisms in bladder cancer seems to have a predictive value because of the evident relationship between the DNA damage response induced by environmental mutagens and cancer predisposition.Objective: The objective was to determine OGG1 Ser326Cys, XRCC1 Arg399Gln, XPD Asp312Asn, and ERCC6 Met1097Val polymorphisms in bladder cancer patients as compared to controls.Methods: Both groups were predominantly represented by Belarusians and Eastern Slavs. DNA samples from 336 patients and 370 controls were genotyped using a PCR-RFLP method.Results: The genotype distributions were in agreement with the Hardy–Weinberg equilibrium. The minor allele frequencies in the control population were in the range of those in Caucasians in contrast to Asians. The OGG1 326 Ser/Cys and XPD 312 Asp/Asn heterozygous genotypes were inversely associated with cancer risk (OR [95% CI] = 0.69 [0.50–0.95] and 1.35 [1.0–1.82], respectively). The contrasting effects of these genotypes were potentiated due to their interactions with smoking habit or age.Conclusions: Among four DNA repair gene polymorphisms, the OGG1 326 Ser/Cys and XPD 312 Asp/Asn heterozygous genotypes might be recognized as potential genetic markers modifying susceptibility to bladder cancer in Belarus.

The polymorphism of DNA repair genes XPD, XRCC1, OGG1, and ERCC6, life expectancy, and the inclination to smoke

The polymorphism of excision repair genes XPD Asp312Asn, XRCC1 Arg399Gln, OGG1 Ser326Cys, and ERCC6 Met1097Val was analyzed by PCR-RFLP in 370 representatives of the Belarusian population of average, old, and elderly ages. Correlation analysis showed that the frequencies of wild-type homozygous combinations significantly increase with age in the group of subjects over 70 years old in the case of the interaction of two genes, XPD 312 and XRCC1399, or three genes, XPD312, XRCC1399, and ERCC6 1097. In a subgroup of the long-lived, this relationship is manifested in case of a pairwise interaction of gene XPD 312 with XRCC1 399 or ERCC6 1097, as well as an interaction of three genes, XPD 312, XRCC1 399, and ERCC6 1097. The data suggest that the optimum activity of repair processes may favor longevity. It is shown that the frequency of the Asp/Asp genotype is reduced, and the frequency of the Asn allele of the XPD 312 gene is increased in the subgroup of smokers as compared with nonsmokers, which apparently indicates an association of this gene polymorphism with an inclination to smoke. The problem requires further study.

Polymorphisms of DNA repair genes XPD, XRCC1, and OGG1, and lung adenocarcinoma susceptibility in Chinese population

Lung adenocarcinoma (ADC) is one of the major histological types of lung cancer. Genetic polymorphism in DNA repair genes and lung ADC susceptibility is well documented. In this case-control study, the association between the polymorphic sites of DNA repair genes XPD-751, XRCC1-399, and OGG1-326, and lung ADC susceptibility in ethnic Han Chinese population has been investigated. Genomic DNA was isolated from the peripheral blood of 201 healthy controls and 82 lung ADC patients from the people of Hunan Province, China. Polymorphisms of the investigated genes were analyzed by using polymerase chain reaction-restriction fragment length polymorphism. There was no significant difference between the samples from lung ADC patients and healthy controls about the genotype frequencies of XPD-751, XRCC1-399, and OGG1-326 sites. However, multifactor dimensionality reduction analysis showed that the genetic polymorphisms of the three-loci models of DNA repair genes (XPD-751/XRCC1-399/OGG1-326) are associated with lung ADC. Thus, this study reveals that a three-order interaction among the polymorphic sites of XPD-751, XRCC1-399, and OGG1-326 is associated with lung ADC risk in the studied population, although polymorphism in individual gene was not associated.

DNA Repair Genes XRCC1, XRCC3, XPD, and OGG1 Polymorphisms among the Central Region Population of Saudi Arabia

DNA repair is one of the central defense mechanisms against mutagenic exposures. Inherited SNPs of DNA repair genes may contribute to variations in DNA repair capacity and susceptibility to cancer. Due to the presence of these variants, inter-individual and ethnic differences in DNA repair capacity have been established in various populations. Saudi Arabia harbors enormous genetic and cultural diversity. In the present study we aimed to determine the genotype and allele frequencies of XRCC1 Arg399Gln (rs25487), XRCC3 Thr241Met (rs861539), XPD Lys751Gln (rs13181), and OGG1 Ser326Cys (rs1052133) gene polymorphisms in 386 healthy individuals residing in the central region of Saudi Arabia and compare them with HapMap and other populations. The genotype and allele frequencies of the four DNA repair gene loci in central Saudi population showed a distinctive pattern. Furthermore, comparison of polymorphisms in these genes with other populations also showed a unique pattern for the central Saudi population. To the best of our knowledge, this is the first report that deals with these DNA repair gene polymorphisms among the central Saudi population.

DNA Repair Gene ERCC1 and XPD Polymorphisms Predict Glioma Susceptibility and Prognosis

We conducted a case-control study in a Chinese population to clarify the association between polymorphisms in ERCC1 and XPD and susceptibility and survival of glioma. A total of 393 cases and 410 controls were selected from March 2007 to December 2011. Genotyping of ERCC1 and XPD was conducted by TaqMan assays using the ABI Prism 7911HT Sequence Detection System. All analyses were performed using the STATA statistical package. Polymorphisms in ERCC1 118C/T, ERCC1 8092C/A and XPD Asp312Asn showed no statistically significant difference between glioma cases and controls. However, individuals with the XPD 751Gln/Gln genotype had an increased risk of developing glioma compared with those with the Lys/Lys genotype (adjusted OR=1.64, 95% CI: 1.06-2.89). The ERCC1 118T/T genotype was associated with significantly higher median survival than the ERCC1 C/C genotype (HR=0.67, 95%CI=0.35-0.96). In addition, individuals with XPD 751Gln/Gln had a lower median survival time than XPD Lys/Lys carriers (HR=0.54, 95%CI=0.37- 0.93). In conclusion, we observed that the XPD 751Gln/Gln genotype is associated with glioma susceptibility, and ERCC1 118 T/T and XPD 751Gln/Gln genotypes confer a significantly better prognosis.

P-0178 Genetic Analysis of the Dna Repair Gene Xpd (LYS751GLN) and XRCC1 (ARG399GLN) in Romanians with Sporadic Colorectal Cancer

ABSTRACT Introduction Carcinogenesis is a complex process in which genomic instability is affected. The most important processes involved in DNA damage repair are the excision of defective bases - base excision repair (BER pathways) and the excision of the entire defective nucleotide – nucleotide excision repair (NER pathways). Two of the most important proteins involved in the BER and NER, respectively pathway are the X-ray cross-complementation group 1-XRCC1 and the Xeroderma pigmentosum group D protein-XPD Aim: to analyze the distribution of genetic polymorphisms in genes coding for DNA repair enzymes XPD (Lys751Gln) and XRCC1 (Arg399Gln) in Romanian patients with sporadic colorectal cancer (CCR) as compared to control subjects, both females and males; to establish the most frequent haplotype associated with sporadic CCR risk in Romanians; to check for the association with the different stages of carcinomas, as well as with the prognosis of sporadic CCR. Methods 312 samples were collected, of which 150 were sporadic CCR cases (80 female and 70 male patients) and 162 were controls (100 females and 62 males); Genotyped were done by PCR-RFLP analysis. The differences in genotype and allele frequencies between the group of patients with sporadic CCR and the control group were also examined using SPSS® Software version 12 for Windows (SPSS Inc., Chicago Illinois, USA 1989- 2003). Results The risk to develop sporadic CRC was 3.09 (p=0.02) and 3.49 (p=0.001), respectively, in association with the homozygous Gln/Gln-XPD and Gln/Gln-XRCC1 genotype. Also significantly higher risk to develop sporadic CRC was found in females homozygous for Gln/Gln-XPD (OR 3.43, p=0.04) and Gln/Gln-XRCC1 (OR 3.32, p=0.018) genotype and in males homozygous for Gln/Gln-XRCC1 (OR 3.63, p=0.04) genotype. The combined effect of the two polymorphisms on sporadic CRC risk was also evaluated through the construction of haplotypes. A significantly higher risk for sporadic CRC in association with Lys/Gln-Arg/Gln (22% vs. 7.4%, OR 3.52, p Conclusion Genetic variations affecting DNA repair capacity increase the risk for sporadic colorectal cancer in Romanians. The XPD and XRCC1 mutations could be associated with more aggressive forms of sporadic colorectal cancer and positive patients have a worse prognosis compared to negative patients.

Influence of consumption of allyl isothiocyanate or cabbage and mustard on DNA integrity in humans

Allyl isothiocyanate (AITC), which is derived from Brassica vegetables, is associated with anti‐cancer effects, though much evidence is from cell studies. A feeding study was conducted to investigate the effect of AITC on DNA integrity in vivo. Adults (n=46) consumed AITC, AITC‐rich foods (cabbage and mustard (C/M)), or a control diet for 10 d each in a crossover design. Volunteers were genotyped for the deleted or functional alleles of GSTM1 and GSTT1, and SNPs Asp312Asn and Lys751Gln in the DNA repair gene XPD. Ten day intake of neither AITC nor C/M resulted in significant differences in DNA strand breaks in peripheral blood mononuclear cells (LSmean % DNA in tail ± SEM: 4.8±0.6 for control, 5.7±0.7 for AITC, 5.3±0.6 for C/M). However, both AITC and C/M increased DNA strand breaks 3 h post‐consumption (%DNA in tail: 3.2±0.7 for control, 8.3±1.7 for AITC, 8.0±1.7 for C/M), and this difference disappeared at 6 h (4.2±0.9 for control, 5.7±1.2 for AITC, 5.5±1.2 for C/M). Genotypes for GSTM1, GSTT1, and XPD were not associated with treatment effects. In summary, DNA damage appeared to be induced in the short term by AITC and AITC‐rich products, but that damage disappeared quickly. Funded by USDA and NCI.

Genetic variation in nucleotide excision repair pathway genes influence prostate and bladder cancer susceptibility in North Indian population

BACKGROUND:Inherited polymorphisms of XPD and XPC genes may contribute to subtle variations in NER DNA repair capacity and genetic susceptibility to development of urological cancer such as prostate and bladder cancer.MATERIALS AND METHODS:We genotyped four Single Nucleotide Polymorphs (SNPs) of the DNA repair gene XPD and XPC in 195 prostate cancer (PCa) and 212 bladder cancer (BC) patients and 250 healthy controls from the same area. XPD Exon 10 (G>A) by amplification refractory mutation system and Exon 23 (A>C), XPC Intron 9 (Ins/Del) and Exon 15 (A>C) were genotyped by PCR-RFLP.RESULTS:Variant genotype of XPC demonstrated association with PCa as well as in BC (P, 0.013; P, 0.003). Combined genotype (GA+AA) revealed association with PCa and in BC (P, 0.012, P, 0.002). Variant allele also demonstrated risk in both the cancer. Diplotype of XPD and XPC was associated with a significant increase in PCa and BC risk. Variant (+/+) genotype of XPC intron 9 shown increased risk with PCa and in BC (P, 0.012; P, 0.032). CC genotype of XPC exon 15 revealed increase risk (P, 0.047) with PCa not in BC. In clinopathological grade variant allele of XPC intron 9 and 15 demonstrated risk with high grade of tumor and bone metastasis of PCa. In BC variant allele of XPD exon 10 and 15 also shown association with tumor grade. XPC intron 9 influences the risk of BC in former tobacco users in BC.CONCLUSIONS:Our result support that SNPs in XPD and XPC gene may reduce NER repair capacity and play a major role for PCa and BC in North India.

DNA repair gene XPD and XRCC1 polymorphisms and the risk of febrile neutropenia and mucositis in children with leukemia and lymphoma

The aim of the study is to investigate association between DNA repair gene XPD and XRCC1 polymorphisms and febrile neutropenia (FN) and mucositis. The study population consisted of 29 children with Burkitt lymphoma and 61 children with acute lymphoblastic leukemia. Analysis revealed that XRCC1194Trp allele showed a protective effect against longer FN and mucositis. There was also statistically increased risk for severe mucositis in patients with XRCC1Arg399Gln polymorphism. There are no studies that have examined this relationship before. Further studies with larger cohorts are needed to clarify the association.

Evaluating chromosomal damage in workers exposed to hexavalent chromium and the modulating role of polymorphisms of DNA repair genes

Welders have been chronically exposed to hexavalent chromium with potential consequences on chromosomal integrity. Our study is focused on the extent of any such chromosomal aberrations with respect to chromium levels in the blood of welders as well as on the tentative modulating role of polymorphisms in DNA repair genes XPD Lys751Gln, XPG Asn114His, XPC Lys939Gln, hOGG1 Ser326Cys and XRCC1 Arg399Gln on chromosomal damage. The study was conducted on 144 individuals consisting of 73 welders exposed to chromium for 10.2 ± 1.67 years and 71 control individuals without known exposures. Chromosomal aberrations, their chromatid-type and chromosome-type aberrations were detected by conventional cytogenetic analysis. XPD, XPG, XPC, hOGG1 and XRCC1 gene polymorphisms were assayed for by Taqman SNP genotyping assay ("Assay-by-Demand") using Real-Time allelic discrimination on AB 7500 equipment. Chromium concentration in the blood was determined by atomic absorption spectrophotometry. The level of chromium in the blood of welders ranged between 0.032 and 0.182 μmol l(-1) and was significantly higher than that in controls (0.07 ± 0.04 μmol l(-1) vs. 0.03 ± 0.007 μmol l(-1)). Parameters of chromosomal damage were similar in both the exposed and the control individuals (1.89% vs. 1.70% for total chromosomal aberrations, 0.97% vs. 0.88% for chromosome-type and 0.92% vs. 0.80% for chromatid-type, respectively). Chromatid-type of aberrations positively correlated with the level of chromium in the blood (r = 0.28; P = 0.02). Significantly higher total chromosomal aberrations were detected in individuals with homozygous variant polymorphism in XRCC1 Arg399Gln gene as compared to those with heterozygous and homozygous wild-type genotypes (2.20, 1.89 and 1.48%, respectively; P = 0.01). A similar tendency was found for chromatid-type aberrations (1.30% for homozygous variant genotype bearers, 0.94% for those with heterozygous genotype and 0.75% for carriers of homozygous wild-type genotype, respectively; P = 0.04). Although no apparent increase in chromosomal damage was recorded in chromium-exposed welders in comparison with controls, genetic make-up in DNA repair genes may increase susceptibility toward adverse effect of chromium.

Association Between Polymorphisms of ERCC1 and XPD and Clinical Response to Platinum-Based Chemotherapy in Advanced Non–Small Cell Lung Cancer

DNA repair capacity is correlated with sensitivity of cancer cells toward platinum-based chemotherapy. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in polymorphisms of DNA repair gene ERCC1 (excision repair cross-complementation group 1) and XPD (ERCC2, excision repair cross-complementation group 2) were associated with the tumor response in advanced non-small-cell lung cancer (NSCLC) patients received platinum-based chemotherapy in Chinese population. Totally 115 patients with advanced NSCLC were routinely treated with cisplatin- or carboplatin-based chemotherapy, and clinical response was evaluated after 2 cycles. Three dimensions (3-D) polyacrylamide gel-based DNA microarray method was used to evaluate the genotypes of ERCC1 Asn118Asn (354 CT), Gln504Lys (8092 CA) and XPD Lys751Gln (35931 AC). The C→T change of ERCC1 Asn118Asn polymorphism and the C→A change of ERCC1 Gln504Lys polymorphism have statistically significant association with elevated or descendent platinum-based chemotherapy response respectively. The polymorphic status of ERCC1 might be the promising ancillary marker for predicting treatment response of advanced stage NSCLC patients. The DNA microarray-based method is accurate, high-throughput and inexpensive, suitable for SNP genotyping in a large number of individuals.