魏庆义
博士研究生 教授
Department of Epidemiology
人类肿瘤遗传易感性与环境致癌分子机理
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- 姓名:魏庆义
- 目前身份:在职研究人员
- 担任导师情况:
- 学位:
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学术头衔:
博士生导师, ,
- 职称:高级-教授
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学科领域:
肿瘤学
- 研究兴趣:人类肿瘤遗传易感性与环境致癌分子机理
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425
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成果数
10
魏庆义, Yawei Qiao a, Margaret R. Spitz a, Zhaozheng Guoa, Mohammad Hadeyati b, Lawrence Grossman b, Kenneth H. Kraemer c, Qingyi Wei a, *
Mutation Research 509(2002)165-174,-0001,():
-1年11月30日
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.
Host-cell reactivation, DNA repair, Genetic susceptibility, Genotype, Molecular epidemiology
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魏庆义, Changping Zou a, Yongli Guan b, Changchun Zou c, Jian Wang a, Li-E. Wang b, Monica Liebert d, H. Barton Grossman d, Qingyi Wei b, *
Cancer Letters 180(2002)131-137,-0001,():
-1年11月30日
We previously demonstrated that N-(4-hydroxyphenyl)retinamide (4-HPR) and gamma-irradiation, when used in combination, had a synergistic effect in inducing apoptosis in bladder cancer cells, suggesting that 4-HPR may increase radiosensitivity in bladder cancer cells. To unravel molecular correlates in this radiosensitizing effect of 4-HPR, we examined the baseline and 4-HPR-induced expression of GADD45 to elucidate possible mechanisms by which 4-HPR enhanced the effect of gammairradiation in three bladder cancer cell lines. To investigate the role of p53 in mediating the radiosensitizing effect of 4-HPR, we also examined mutations in exons 5-9 by using direct sequencing and the levels of p53 expression by using RT-PCR and Western blot, before and after treatment with 4-HPR in these bladder cancer cell lines. Two cell lines had low expression of GADD45, and a dose-dependent increase in GADD45 expression induced by 4-HPR was found in bladder cancer cell lines without p53 mutations in exons 5-9. A combination of gamma-irradiation and 4-HPR showed a significantly greater effect in enhancing GADD45 expression than either agent used alone. The results indicate that the combined treatment with 4-HPR and gamma-irradiation has a stronger effect on GADD45 expression than the treatment with either agent alone, which suggests that the two agents may have an additive/synergistic effect. However, a normal p53 function appears to be necessary for the dosedependent induction of GADD45 by 4-HPR. Once our results are verified and replicated by other investigators, 4-HPR may have a potential clinical implication in effectively treating bladder cancer in combination with low-gamma-irradiation therapy.
Apoptosis, Chemoprevention, DNA damage, DNA repair, Radiosensitivity
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【期刊论文】γ-Radiation Sensitivity and Risk of Glioma
魏庆义, Melissa L. Bondy, Li-E. Wang, Randa El-Zein, Mariza de Andrade, Mano S. Selvan, Janet M. Bruner, Victor A. Levin, W. K. Alfred Yung, Phyllis Adatto, Qingyi Wei
Journal of the National Cancer Institute, Vol. 93, No.20, October 17, 2001,-0001,():
-1年11月30日
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【期刊论文】Cyclin D1 Polymorphism and Increased Risk of Colorectal Cancer at Young Age
魏庆义, Shouming Kong, Qingyi Wei, Christopher I. Amos, Patrick M. Lynch, Bernard Levin, Jihong Zong, Marsha L. Frazier
Journal of the National Cancer Institute, Vol. 93, No.14, July 18, 2001,-0001,():
-1年11月30日
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魏庆义, Margaret R. Spitz, Xifeng Wu, Yunfei Wang, Li-E Wang, Sanjay Shete, Christopher I. Amos, Zhaozheng Guo, Lei Lei, Harvey Mohrenweiser, and Qingyi Wei
[CANCER RESEARCH 61, 1354-1357, February 15, 2001],-0001,():
-1年11月30日
%; P<0.001), which represents an average 18% reduction among the cases. The variant Lys751Gln and Asp312Asn allele frequencies were 0.36 and 0.29, respectively, for the cases and 0.33 and 0.27, respectively, for the controls. For subjects homozygous for the variant genotype at either locus, the adjusted odds ratio [95% confidence interval (CI)] was 1.84 (1.11-3.04; P 5-0.018, for trend). Both cases and controls with the wild-type genotypes exhibited the most proficient DRC. The risk (95% CI) for suboptimal DRC (defined as less than the median DRC value among the controls) was 1.57 (0.743.35) for those with the Gln/Gln751 genotype. For cases with the Asn/Asn312 genotype, the risk (95% CI) was 3.50 (1.06–11.59). For cases who were homozygous at either locus, the risk was 2.29 (1.03-5.12; P 5-0.048, for trend). The pattern was less evident among the controls, although there was a nonsignificant 41% increase in the risk of suboptimal DRC for controls who were homozygous at either locus. These results suggest that the two XPD polymorphisms have a modulating effect on DRC, especially in the cases.
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魏庆义, Donghui Li, Pervez F. Firozi, Li-E Wang, Carol H. Bosken, Margaret R. Spitz, Waun Ki Hong, and Qingyi Wei
[CANCER RESEARCH 61, 1445-1450, February 15, 2001],-0001,():
-1年11月30日
adducts in the host cells. Overall, the patients had significantly higher levels of BPDE-DNA adducts than did the controls (mean 6 SD per 107 nucleotides, 93.2 6 89.3 for cases versus 63.7 6 61.1 for controls; P 5 0.001). Univariate and multivariate logistic regression analyses were performed to calculate the crude and adjusted odds ratios and their 95% confidence intervals. When the median adduct level of controls (46/107 nucleotides) was used as the cutoff point, 64% of cases had higher levels (odds ratio, 2.15; 95% confidence interval, 1.39 –3.33, adjusted for age, sex, ethnicity, body mass index, recent weight loss, pack-years smoked, smoking in the last 24h, and family history of cancer). Stratified analyses showed consistently higher levels of BPDE-induced adducts in cases than in controls, regardless of subgroup of age, sex, ethnicity, body mass index, recent weight loss, pack-years smoked, smoking in the last 24h, and family history of cancer. A significant dose-response relationship between the quartile levels of BPDE-induced DNA adducts and the risk of lung cancer was observed (trend test, P<0.001). The significant association between the level of in vitro BPDE-induced DNA adducts and risk for lung cancer suggests that subjects very sensitive to BPDE-induced DNA damage may have a suboptimal ability to remove the BPDE-DNA adducts and so are susceptible to tobacco carcinogen exposure and, therefore, may be at increased risk of
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魏庆义, Ping Xiong, Melissa L. Bondy, Donghui Li, Hongbing Shen, Li-E Wang, S. Eva Singletary, Margaret R. Spitz, and Qingyi Wei
[CANCER RESEARCH 61, 8465-8469, December 1, 2001],-0001,():
-1年11月30日
Mounting epidemiological evidence suggests that smoking may play a role in the etiology of breast cancer. Because smoking-related DNA adducts are detectable in both normal and malignant breast tissues, we hypothesized that breast cancer patients may be sensitive to tobaccoinduced carcinogenesis, and this sensitivity could be modulated by variants of metabolic genes. To test this hypothesis, we evaluated benzo-(a)pyrene diol-epoxide (BPDE)-induced mutagen sensitivity and polymorphisms of GSTM1 and GSTT1 in a pilot case-control study of breast cancer. Short-term cell cultures were established from blood samples of 100 female breast cancer patients and 105 healthy controls. After 5 h of in vitro exposure to 4M of BPDE, we harvested the lymphocytes for cytogenetic evaluation and recorded and compared the frequency of BPDE-induced chromatid breaks between cases and controls. We used a multiplex PCR-based assay to simultaneously detect polymorphisms of GSTM1 and GSTT1 from genomic DNA. We performed univariate and multivariate logistic regression analyses and calculated odds ratios (OR) and 95% confidence intervals (CIs). Cases had a significantly higher frequency of chromatid breaks than did controls (P<0.0001). The level of chromatid breaks greater than the median value of controls was associated with a >3-fold increased risk of breast cancer [adjusted odds ratio (ORadj) [1] 3.11; 95% CI [1] 1.72-5.64]. The risk was more pronounced in those who were<45 years (ORadj [1] 4.79; 95% CI [1] 1.87- 12.3), ever-smokers (ORadj [1] 5.55; 95% CI [1] 1.85-16.6), alcohol drinkers (ORadj [1] 4.64; 95% CI [1] 1.70-12.7), and those who had the GSTT1 null variant (ORadj [1] 8.01; 95% CI [1] 1.16-55.3). These data suggest that sensitivity to BPDE-induced chromosomal aberrations may contribute to the risk of developing breast cancer, and such sensitivity may be modulated by both genetic and environmental factors. Larger studies are needed to confirm our findings.
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魏庆义, Hongbing Shen, Erich M. Sturgis, Sikandar G. Khan, Yawei Qiao, Tala Shahlavi, Susan A. Eicher, Yiaochu Xu, Xinru Wang, Sara S. Strom, Margaret R. Spitz, Kenneth H. Kraemer, and Qingyi Wei
CANCER RESEARCH 61, 3321-3325, April 15, 2001,-0001,():
-1年11月30日
Inherited polymorphisms of DNA repair genes may contribute to variations in DNA repair capacity and genetic susceptibility to cancer. In a hospital-based case-control study of 287 non-Hispanic white patients with newly diagnosed SCCHN and 311 control subjects matched on age, sex, ethnicity, and smoking status, we investigated the role of a newly identified variant allele of XPC, XPC-PAT1. We found that the frequency of the XPC-PAT1 allele was higher in the cases (0.409) than in the controls (0.333; P 5 0.007). Fifty cases (17.4%) and 37 controls (11.9%) were XPC-PAT1/1, and 135 (47.0%) cases and 133 controls (42.8%) were XPC-PAT1/2. XPC-PAT1/2 and XPC-PAT1/1 subjects were at significantly increased risk for SCCHN [adjusted odds ratios 5 1.44 and 1.85, respectively (95% confidence intervals, 1.01-2.05 and 1.12-3.05, respectively; trend test, P 5 0.007)]. We did not find ethnic difference in the frequency of XPC-PAT1 allele among four groups aged between 19 and 75 years: non-Hispanic whites, 294; African-Americans, 178; Hispanic-Americans, 103; and native Chinese, 119 (0.333, 0.281, 0.296, and 0.353, XPC-PAT1 allele may contribute to the risk of developing SCCHN.
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魏庆义, Erich M. Sturgis, Kristina R. Dahlstrom, Yongli Guan, Susan A. Eicher, Sara S. Strom, Margaret R. Spitz, and Qingyi Wei
Cancer Epidemiology, Biomarkers & Prevention, Vol. 10, 273-275, March 2001,-0001,():
-1年11月30日
Alcohol is one of the major risk factors for oral and pharyngeal cancer. The rate-limiting step in alcohol metabolism is the oxidation (activation) of ethanol to acetaldehyde by the alcohol dehydrogenases (ADHs). It has been hypothesized that individuals who are homozygous for the fast allele (ADH3 1-1) are at greater risk for alcohol-related cancers. To test this hypothesis,we investigated the association between the ADH3 genotype and oral and pharyngeal cancer risk in a large racially homogeneous case-control study of 229 patients and 575 matched control subjects with frequency matching on age, sex, and smoking status. Although the smoking status was matched between cases and controls, current and former alcohol use remained a significant risk factor, compared with never use (odds ratio, 2.08; 95% confidence interval, 1.37-3.17; odds ratio, 1.97; 95% confidence interval, 1.25-3.09; and odds ratio, 1.00, respectively). The ADH3 1 allele frequency of controls was 57.4%, consistent with reports of similar racial groups (50-60%). The genotype distribution in controls was also consistent with the Hardy-Weinberg equilibrium (P 5 0.51). However, the ADH3 1 allele frequency and ADH3 1-1 genotype frequency were not significantly different between cases and controls [55.5% versus 57.4% (P 5 0.52), and 30.6% versus 31.3% (P 5 0.91), respectively]. There was no association between ADH3 genotypes (ADH3 1-1, ADH3 1-2, and ADH3 2-2) and risk of oral and pharyngeal cancer (odds ratios, 1.00; 0.96; 95% confidence interval, 0.68-1.37; and odds ratio, 1.23; confidence interval, 0.78-1.93, respectively). Therefore, we found no evidence that supports a main effect of ADH3 genotype or a combined effect of alcohol and ADH3 genotype on risk of cancer of the oral cavity or pharynx.
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魏庆义, Hongbing Shen, Margaret R. Spitz, Li-E Wang, Waun K. Hong, and Qingyi Wei
Cancer Epidemiology, Biomarkers & Prevention, Vol. 10, 397-401, April 2001,-0001,():
-1年11月30日
Previous studies have suggested that low folate intake is associated with increased risk of lung cancer. Methylenetetrahydrofolate reductase (MTHFR) is one of the enzymes involved in folate metabolism and is thought to influence DNA methylation and nucleotide synthesis. MTHFR is highly polymorphic, and the variant genotypes result in decreased MTHFR enzyme activity and lower plasma folate level. Therefore, we hypothesized that these variant genotypes may play a role in the etiology of lung cancer. To test this hypothesis, we investigated the association between two common MTHFR polymorphisms (C677T and A1298C) and risk of lung cancer in a nonpopulation- based case-control study of 550 histologically confirmed lung cancer cases and 554 healthy controls. The subjects were non-Hispanic whites, and the controls were frequency-matched to the cases by age (65 years), sex, and smoking status (ever or never). Folate intake and alcohol consumption were estimated from a selfadministered food-frequency questionnaire. The cases consumed significantly less folate (162mg/day/1000 kcal) than the controls did (172mg/day/1000 kcal; P 5 0.033). However, we found no evidence for an association between the MTHFR C677T and A1298C polymorphisms and risk of lung cancer in either all of the subjects or the low folate intake subgroup; nor did we find evidence for an interaction between these two MTHFR polymorphisms and dietary folate intake or alcohol use. In multivariate logistic regression analysis, the adjusted odds ratios and 95% confidence intervals for MTHFR C677T were 1.1 (0.8-1.4) for 677CT versus 677CC wild type and 1.1 (0.7-1.7) for 677TT versus 677CC, and for MTHFR A1298C, they were 1.0 (0.8-1.3) for 1298AC versus 1298AA wild type and 1.1 (0.7-1.8) for 1298CC versus 1298AA. These MTHFR enzyme activity of those with the 677CC wild-type genotype, whereas heterozygotes (677CT) have about 65% ofnormal enzyme activity (15). Up to 15% of the population is homozygous 677TT for the variant, which is associated with higher plasma homocysteine levels and reduced plasma folate levels (16). The second common MTHFR polymorphism, a glutamate to alanine (A3 C) change at position 1298, also influences the specific activity of the enzyme, homocysteine levels, and plasma folate concentration but to a lesser extent than the C677T polymorphism does (14). Previous studies (17) of colorectal cancer reported a significantly decreased risk of colorectal cancer associated with the 677TT genotype that was not observed among those with low folate intakes or serum levels. Recently, another study (18) reported that individuals with the MTHFR 677TT, 1298AC, and 1298CC genotypes have reduced risk of adult acute lymphocytic leukemia. However, the association between these two common MTHFR polymorphisms and the risk of lung cancer has not been examined. Because the MTHFR polymorphisms reduce enzyme activity and low dietary intake of folate is associated with increased risk of lung cancer, we hypothesized that the MTHFR polymorphisms are associated with risk of lung cancer. We tested this hypothesis by genotyping our specimens from a non-population-based case-control study of lung cancer for these two MTHFR polymorphisms.
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