Showing papers by "Qingyi Wei published in 2002"

Modulation of repair of ultraviolet damage in the host-cell reactivation assay by polymorphic XPC and XPD/ERCC2 genotypes.

Abstract: DNA repair capacity (DRC) plays an important role in genetic susceptibility to cancer. Polymorphisms of a number of DNA repair genes involved in several distinct pathways have been identified. However, their effects on repair function have not been well characterized. We demonstrated previously that DRC for removal of benzo[a]pyrene diol epoxide-induced DNA damage measured by a host-cell reactivation assay was modulated by two XPD/ERCC2 polymorphisms in lung cancer. In this report, we investigated the association between the repair phenotype of ultraviolet (UV)-induced damage and genotypes of three DNA repair genes, XPC and XPD [involved in nucleotide excision repair (NER)] and XRCC1 [involved in base excision repair (BER)]. We measured DRC for removal of UV photoproducts by the host-cell reactivation assay in cryopreserved lymphocytes from 102 healthy non-Hispanic white subjects. We also typed these subjects for five polymorphisms in these three DNA repair genes (at intron 9 of XPC; exons 6, 10 and 23 of XPD and exon 10 of XRCC1). Compared with wild-type homozygotes, subjects homozygous for polymorphisms of the two NER genes consistently had suboptimal DRC. The DRC was consistently lower in subjects homozygous for XPC, XPD or both than in subjects with other genotypes, although the difference was not statistically significant for XPD variants. In contrast, the polymorphic allele of the BER gene, XRCC1, had no consistent effect on DRC. We concluded that these NER polymorphisms may modulate DRC and may be useful biomarkers for identifying individuals at risk of developing cancer.

A novel polymorphism in human cytosine DNA-methyltransferase-3B promoter is associated with an increased risk of lung cancer.

Abstract: DNA repair is central to genomic integrity. Reduced expression of several nucleotide excision repair genes has been demonstrated to be associated with increased risk of lung cancer. Because methylation of gene promoters is one of the major regulatory mechanisms of gene expression and most nucleotide excision repair gene promoters have not been fully characterized, we hypothesized that genetic variants of the genes that are responsible for regulating genomic methylation are associated with increased risk of lung cancer. Recently, we identified a C→T transition at a novel promoter region of cytosine DNA-methyltransferase-3B (DNMT3B) and found that this polymorphic transition significantly increases the promoter activity. In this hospital-based case-control study of 319 patients with incident lung cancer and 340 healthy controls frequency matched on age (±5 years), sex, ethnicity, and smoking status, we genotyped subjects for this DNMT3B promoter polymorphism to determine the association between this genetic variant and risk of lung cancer. Compared with CC homozygotes, CT heterozygotes had a >2-fold increased risk of lung cancer [adjusted odds ratio (OR), 2.13; 95% confidence interval (CI), 1.47–3.08] and TT homozygotes an OR of 1.42 (95% CI, 0.91–2.21). The combined variant genotype (CT + TT) was associated with a nearly 2-fold increased risk (adjusted OR, 1.88; 95% CI, 1.32–2.66). These results suggest that this novel variant of DNMT3B is associated with increased risk of lung cancer and may contribute to identifying individuals genetically susceptible to tobacco-induced cancers. Additional studies on the underlying molecular mechanism of this polymorphism are warranted.

An Analysis of DNA Repair as a Determinant of Survival in Patients With Non-Small-Cell Lung Cancer

Abstract: Background: Non-small-cell lung cancer (NSCLC) is frequently resistant to chemotherapy, and this resistance has been associated with elevated nucleotide excision repair (NER) in tumor tissue. We hypothesized that patients with NSCLC who had effective systemic (host) NER would have poorer survival than patients with suboptimal NER and that the association between NER effectiveness and survival would be most marked in patients receiving chemotherapy. Methods: 375 patients with newly diagnosed NSCLC were accrued for a case-control study between July 1995 and December 1999. NER activity was estimated as the DNA repair capacity (DRC) measured in the patient's peripheral lymphocytes by the host cell reactivation assay. Cox proportional hazards models were used to assess the association between DRC and survival. All statistical tests were two-sided. Results: For every unit (percentage) increase in DRC, the relative risk (RR) of death was 1.05 (95% confidence interval [CI] = 1.00 to 1.10; P = .05) for the 345 patients for whom weight loss information was available and 1.06 (95% CI = 1.00 to 1.12; P = .03) for the 275 patients with complete follow-up information. In 86 patients treated with chemotherapy only, the RR of death increased to 1.11 (95% CI = 1.02 to 1.21; P = .01) for every unit (percentage) increase in DRC. Of those 86 patients, patients in the top quartile of the DRC distribution were at twice the RR of death as those in the lowest quartile (RR = 2.72; 95% CI = 1.24 to 5.95; P = .01). Effective DRC was not a risk factor for death in patients who were not treated with chemotherapy. Conclusions: Our data suggest that effective host DRC may be associated with poorer survival in patients with NSCLC who are treated with chemotherapy.

Rapid assessment of repair of ultraviolet DNA damage with a modified host-cell reactivation assay using a luciferase reporter gene and correlation with polymorphisms of DNA repair genes in normal human lymphocytes.

Abstract: As DNA repair plays an important role in genetic susceptibility to cancer, assessment of the DNA repair phenotype is critical for molecular epidemiological studies of cancer. In this report, we compared use of the luciferase (luc) reporter gene in a host-cell reactivation (HCR) (LUC) assay of repair of ultraviolet (UV) damage to DNA to use of the chloramphenicol (cat) gene-based HCR (CAT) assay we used previously for case-control studies. We performed both the assays on cryopreserved lymphocytes from 102 healthy non-Hispanic white subjects. There was a close correlation between DNA repair capacity (DRC) as measured by the LUC and CAT assays. Although these two assays had similar variation, the LUC assay was faster and more sensitive. We also analyzed the relationship between DRC and the subjects' previously determined genotypes for four polymorphisms of two nucleotide-excision repair (NER) genes (in intron 9 of xeroderma pigmentosum (XP) C and exons 6, 10 and 23 of XPD) and one polymorphism of a base-excision repair gene in exon 10 of X-ray complementing group 1 (XRCC1). The DRC was significantly lower in subjects homozygous for one or more polymorphisms of the two NER genes than in subjects with other genotypes (P=0.010). In contrast, the polymorphic XRCC1 allele had no significant effect on DRC. These results suggest that the post-UV LUC assay measures NER phenotype and that polymorphisms of XPC and XPD genes modulate DRC. For population studies of the DNA repair phenotype, many samples need to be evaluated, and so the LUC assay has several advantages over the CAT assay: the LUC assay was more sensitive, had less variation, was not radioactive, was easier to perform, and required fewer cryopreserved cells. These features make the LUC-based HCR assay suitable for molecular epidemiological studies.

Expression of nucleotide excision repair genes and the risk for squamous cell carcinoma of the head and neck.

Abstract: BACKGROUND Phenotypic differences in the ability to repair genetic damage induced by tobacco carcinogens may reflect genetic differences in susceptibility to squamous cell carcinoma of the head and neck (SCCHN). The objective of this study was to assess the variation in baseline expression of five nucleotide excision repair genes between individuals with SCCHN and cancer free controls. METHODS The authors conducted a hospital-based case–control study of 57 SCCHN patients and 105 cancer free controls. Using peripheral blood lymphocytes, a multiplex reverse transcriptase–polymerase chain reaction assay was used to quantitate in vitro the mRNA levels of five genes (ERCC1, XPB/ERCC3, XPG/ERCC5, CSB/ERCC6, and XPC) involved in the nucleotide excision repair pathway. RESULTS The levels of ERCC1, XPB/ERCC3, XPG/ERCC5, and CSB/ERCC6 transcripts were lower in cases than in controls (P =0.0001, 0.096, 0.001, and 0.0001, respectively). In multivariate logistic regression analysis (adjusting for age, gender, race, smoking status, and alcohol use), low expression of ERCC1, XPB/ERCC3, XPG/ERCC5, and CSB/ERCC6 was associated with a statistically significant increased risk for SCCHN (adjusted odds ratios [95% confidence intervals] 6.42 [2.63–15.69], 2.86 [1.39–5.90], 3.69 [1.73–7.90], and 2.46 [1.19–5.09], respectively). CONCLUSIONS Reduced expression of ERCC1, XPB/ERCC3, XPG/ERCC5, and CSB/ERCC6 is associated with a more than two-fold increased risk of SCCHN. Cancer 2002;94:393–7. © 2002 American Cancer Society.

DNA repair gene ERCC1 and ERCC2/XPD polymorphisms and risk of squamous cell carcinoma of the head and neck.

Abstract: Objective To determine the effect of theERCC1C8092A polymorphism and theERCC2/XPDG23591A polymorphism on the risk of squamous cell carcinoma of the head and neck (SCCHN). Design A hospital-based case-control study. Subjects A total of 330 newly diagnosed case subjects with SCCHN and 330 cancer-free control subjects matched on age (± 5 years), sex, smoking status, and alcohol use. All subjects were non-Hispanic whites. Methods After informed consent was obtained, blood was drawn for genotyping. TheERCC1C8092A polymorphism was typed by single-strand conformational polymorphism analysis. TheERCC2/XPDG23591A polymorphism was typed by polymerase chain reaction–based restriction fragment length polymorphism analysis with the enzymeStyI. The χ2analysis was used to assess differences in genotype and allele frequencies. Multivariate logistic regression analysis was performed to estimate the risk of SCCHN for individuals having these genotypes after adjustment for age, sex, tobacco smoking, and alcohol use. Results The DNA was available and genotyping was ultimately successful for 313 case subjects and 313 control subjects. TheERCC18092CC genotype and theERCC2/XPD23591A allele were associated with nonsignificantly increased risks of SCCHN: odds ratios, 1.15 (95% confidence interval [CI], 0.84-1.59) and 1.28 (95% CI, 0.93-1.76), respectively, whereas having both risk genotypes was associated with an even higher risk of SCCHN: odds ratio, 1.78 (95% CI, 0.99-3.17). When considering both polymorphisms, we found a significant allele dose effect (P= .04). Conclusions These 2 polymorphisms may contribute to the risk of SCCHN, but larger studies are needed to confirm their role in SCCHN. Combining common DNA repair gene polymorphisms into models of genetic risk of SCCHN may improve risk estimates.

Genetic susceptibility--molecular epidemiology of head and neck cancer.

Abstract: In parts of the developing world (South Central Asia in particular), squamous cell carcinoma of the head and neck (SCCHN) is one of the most common malignancies encountered. Although tobacco and alcohol are clearly defined as etiologic factors in these malignancies, clinical observations have suggested that inherited genetic factors put some individuals at increased risk for SCCHN. Emerging data (both phenotypic and genotypic) support this concept of genetic susceptibility to SCCHN and point to differences in DNA repair ability, carcinogen metabolism, and cell cycle control as the systems important to the risk of tobacco-induced malignancies. The ability to identify such high-risk individuals will have major influences on the practice of cancer prevention in the future.

A variant of the DNA repair gene XRCC3 and risk of squamous cell carcinoma of the head and neck: a case-control analysis.

Abstract: Individuals differ in their ability to repair DNA damage induced by carcinogens Studies have shown that polymorphisms in DNA repair genes contribute to individual variation in DNA repair capacity and cancer risk In a hospital-based case-control study, we tested the hypothesis that a C to T variant (Thr241Met) of DNA repair gene X-ray repair cross-complementing group 3 (XRCC3) is associated with risk of developing squamous cell carcinoma of the head and neck (SCCHN) We genotyped for this variant in 367 non-Hispanic white patients newly diagnosed with SCCHN and 354 frequency-matched cancer-free controls Compared with the XRCC3 18067CC and 18607CT genotypes, the variant XRCC3 18067TT genotype was associated with a non-statistically significantly increased risk of SCCHN (adjusted odds ratio [ORadj], 136; 95% confidence interval [CI], 089-208), but this risk was significantly increased among female subjects (ORadj 223, 95% CI, 100-498) and current smokers (ORadj, 226; 95% CI, 102-499) These findings suggest that the variant XRCC3 18067TT genotype may not play a major role in the etiology of SCCHN but may contribute to a subset of SCCHN Larger studies are needed to verify these findings

DNA Repair Gene XRCC3 241Met Variant Is Not Associated with Risk of Cutaneous Malignant Melanoma

Abstract: CMM[3][1] is the most serious form of skin malignancy, causing 7400 deaths in the United States in 2002. Although CMM etiology remains unclear, sporadic CMM is known to be associated with ionizing radiation, such as UV light, that causes various types of DNA damage. The cellular response to DNA

Haplotypes of Two Variants in p16 (CDKN2/MTS-1/INK4a) Exon 3 and Risk of Squamous Cell Carcinoma of the Head and Neck: A Case-Control Study

Abstract: The frequent loss or promoter methylation of the tumor suppressor gene p16 in head and neck cancer suggests an etiologic role of p16 in this disease. Two adjacent polymorphisms of p16 exon 3, C540G and C580T, were identified recently. C540G is associated with low expression of p53, and both polymorphisms are associated with tumor aggressiveness, suggesting a possible functional relevance. We hypothesized that these two polymorphisms, particularly their haplotypes, are associated with the risk of developing squamous cell carcinoma of the head and neck (SCCHN). To test this hypothesis, we conducted a hospital-based case-control study of 208 patients with SCCHN and 224 cancer-free control subjects to evaluate the association between p16 genotypes/haplotypes and the risk of SCCHN, using a PCR-single strand conformation polymorphism-based genotyping assay. However, our results suggested that no significant differences exist in the distribution of p16 C540G and C580T genotypes between cases and controls. For the C540G polymorphism, the CC, CG, and GG genotype frequencies were 76.9%, 22.1%, and 1.0%, respectively, in the cases, compared with 76.8%, 21.9%, and 1.3%, respectively, for the controls. For the C580T polymorphism, the CC, CT, and TT genotype frequencies were 83.6%, 15.9%, and 0.5%, respectively, in the cases, compared with 82.6%, 16.5%, and 0.9%, respectively, for the controls. The frequencies of three predominant 540C/580C, 540G/580C, and 540C/580T haplotype alleles were distributed similarly in the cases (79.6%, 12.0%, and 8.4%) and in the controls (78.6%, 12.3%, and 9.1%). None of these differences were statistically significant. We conclude that these polymorphic p16 genotypes or haplotypes may not play a major role in the etiology of SCCHN, if any. However, our limited sample size and power call for larger studies for additional verification of our findings.

Impact energy dependence of Al13 cluster deposition on Ni(001) surface

Abstract: In this paper, the influence of the impact energy on the initial fabrication of thin films formed by low energy cluster deposition was investigated by molecular dynamics simulation of All 3 clusters depositing on Ni(0 0 1) substrate. In the case of soft-landing, (0.01 eV/atom), clusters are rearranged from I-h symmetry into fcc-like clusters on the surface. Then they aggregate each other, which result in thin film growing in 3D island mode. While, growth will be in layer-by-layer mode at the impact energy of a few electron volt due to the transient lateral spread of cluster atoms induced by dense collision cascade. This effect has been traced to collision cascade inside the cluster. which is enhanced by collision with a hard Ni substrate. (C) 2002 Elsevier Science B.V. All rights reserved.

Molecular dynamics study of ‘contact epitaxy’ in Ag clusters supported on a copper (001) surface

Abstract: In this paper, the formation of heteroepitaxial interfacial layers was investigated by molecular dynamics simulation of soft silver particles landing on the (001) surface of single-crystal copper. In our simulations, the clusters Ag13, Ag55, Ag147 and Ag688 were chosen as projectiles. A small cluster will rearrange into an f.c.c. structure when it is supported on the substrate, due to the large value of its surface/volume ratio. Contact epitaxy appeared in large clusters. The characteristic structure of an epitaxial layer in large silver cluster shows the 〈111〉 direction to be the preferential orientation of heteroepitaxial layers on the surface because of the lattice mismatch between the cluster and the substrate. This was confirmed by studying soft landing events in other systems (Au/Cu and Al/Ni).

Molecular dynamics study of 'contact epitaxy' in Ag clusters supported on a copper (001) surface

Abstract: In this paper, the formation of heteroepitaxial interfacial layers was investigated by molecular dynamics simulation of soft silver particles landing on the (001) surface of single-crystal copper. In our simulations, the clusters Ag-13, Ag-55, Ag-147 and Ag-688 were chosen as projectiles. A small cluster will rearrange into an f.c.c. structure when it is supported on the substrate, due to the large value of its surface/volume ratio. Contact epitaxy appeared in large clusters. The characteristic structure of an epitaxial layer in large silver cluster shows the direction to be the preferential orientation of heteroepitaxial layers on the surface because of the lattice mismatch between the cluster and the substrate. This was confirmed by studying soft landing events in other systems (Au/Cu and Al/Ni). (C) 2002 Elsevier Science B.V. All rights reserved.

Haplotypes of Two Variants in p16 (CDKN2/MTS-1/INK4a ) Exon 3 and Risk of Squamous Cell Carcinoma of the Head and Neck:

Abstract: The frequent loss or promoter methylation of the tumor suppressor gene p16 in head and neck cancer suggests an etiologic role of p16 in this disease. Two adjacent polymorphisms of p16 exon 3, C540G and C580T, were identified recently. C540G is associated with low expression of p53, and both polymorphisms are associated with tumor aggressiveness, suggesting a possible functional relevance. We hypothesized that these two polymorphisms, particularly their haplotypes, are associated with the risk of developing squamous cell carcinoma of the head and neck (SCCHN). To test this hypothesis, we conducted a hospital-based case-control study of 208 patients with SCCHN and 224 cancer-free control subjects to evaluate the association between p16 genotypes/haplotypes and the risk of SCCHN, using a PCR-single strand conformation polymorphism-based genotyping assay. However, our results suggested that no significant differences exist in the distribution of p16 C540G and C580T genotypes between cases and controls. For the C540G polymorphism, the CC, CG, and GG genotype frequencies were 76.9%, 22.1%, and 1.0%, respectively, in the cases, compared with 76.8%, 21.9%, and 1.3%, respectively, for the controls. For the C580T polymorphism, the CC, CT, and TT genotype frequencies were 83.6%, 15.9%, and 0.5%, respectively, in the cases, compared with 82.6%, 16.5%, and 0.9%, respectively, for the controls. The frequencies of three predominant 540C/580C, 540G/580C, and 540C/580T haplotype alleles were distributed similarly in the cases (79.6%, 12.0%, and 8.4%) and in the controls (78.6%, 12.3%, and 9.1%). None of these differences were statistically significant. We conclude that these polymorphic p16 genotypes or haplotypes may not play a major role in the etiology of SCCHN, if any. However, our limited sample size and power call for larger studies for additional verification of our findings.