Immunologic Methods for the Detection of Carcinogen Adducts in Humans

Santella, Regina M.; Yang, X.; Hsieh, Ling Ling; Young, Tie Lan; Xiao, Lu; Stefanidis, Marina; Perera, Frederica P.

doi:10.1007/978-1-4613-0637-5_3

Cited by 66 publications

(86 citation statements)

References 14 publications

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“…This antibody cross-reacts with structurally related PAH-diol epoxide-DNA adducts with different affinities. 17,19 After washing with PBS, a peroxidase-labeled antirabbit ABC kit was used (Vector, Burlingame, CA). After dipping the slides in 1% Triton X-100 (Mallinckrodt, Paris, NY) in PBS for 30 sec, a diaminobenzidine kit (Vector) was used.…”

Section: Subjects and Collection Of Data And Specimensmentioning

confidence: 99%

Polycyclic aromatic hydrocarbon‐DNA adducts in liver tissues of hepatocellular carcinoma patients and controls

Chen

Wang

Lunn

et al. 2002

Intl Journal of Cancer

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104

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HCC is a common cancer and HBV and AFB 1 are welldocumented, major risk factors. Epidemiologic studies have documented that cigarette smoking also contributes to the development of HCC. PAHs are ubiquitous environmental pollutants and products of incomplete combustion. They are present in both mainstream and sidestream cigarette smoke. PAHs are metabolically activated by phase I enzymes, including CYP1A1, into electrophilic reactants (diol epoxides), which covalently bind to DNA to form adducts. Diol epoxides are also substrates for phase II detoxifying enzymes, including GSTM and GSTP. To examine the association between PAH-DNA adducts and HCC, adduct levels were determined in liver tissue by relative staining intensity with an immunoperoxidase method using a polyclonal antiserum against BPDE-modified DNA. Subjects were also genotyped for polymorphism in several genes involved in the metabolism of PAH, including GSTM1 and GSTP1. Liver tissue was collected from patients with histologically confirmed HCC (n ‫؍‬ 105) and from non-HCC controls (n ‫؍‬ 37). There was a significant positive correlation (r ‫؍‬ 0.3, p < 0.01) between adducts in tumor and adjacent nontumor tissues among HCC cases. The risk of HCC was higher after adjustment for age, sex and HBsAg in the group with the highest tertile tissue levels of PAH-DNA adducts (mean relative nuclear staining intensity of tumor and nontumor tissue > 344) than in the group with the lowest tertile (staining < 241, OR ‫؍‬ 3.9, 95% CI ‫؍‬ 1.0 -14.9). Among non-HCC controls, there were no significant associations between adduct levels and cigarette smoking, GSTM1 null genotype and HBsAg positivity. A strikingly increased HCC risk was observed (OR ‫؍‬ 20.3, 95% CI ‫؍‬ 5.0 -81.8) among HBsAg-positive subjects whose PAH-DNA adduct levels were high (mean relative nuclear staining intensity of tumor and nontumor tissue > 301, median of control tissues) compared to HBsAg-negative subjects who had low PAH-DNA adduct levels. 4-ABP-and AFB 1 -DNA adducts had been measured previously in these same tissues. Subjects with elevated DNA adduct levels of PAH, 4-ABP and AFB 1 had a significantly higher HCC risk with an OR of 36.7 (95% CI 7.2-187.2) compared to those who had low DNA adduct levels. These results suggest that PAHs may play a role in human hepatocarcinogenesis in conjunction with HBsAg carrier status, GSTM1 and GSTP1 genotypes and exposure to 4-ABP and AFB 1 . © 2002 Wiley-Liss, Inc.Key words: PAH-DNA adduct; hepatocellular carcinoma; HbsAg; GSTM1; GSTP1 HCC is one of the major malignant neoplasms in the world, especially in sub-Saharan Africa and Southeast Asia, including Taiwan. 1,2 Previous studies have indicated that HCC is an environmentally related cancer, with both viral and chemical carcinogens involved in the multistage process. HBV is hyperendemic in Taiwan and chronic HBV infection has been well documented as an important HCC risk factor. 2,3 In addition to HBV, chronic infection with hepatitis C virus, consumption of dietary aflatoxins and alcohol and low consum...

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Section: Subjects and Collection Of Data And Specimensmentioning

confidence: 99%

Polycyclic aromatic hydrocarbon‐DNA adducts in liver tissues of hepatocellular carcinoma patients and controls

Chen

Wang

Lunn

et al. 2002

Intl Journal of Cancer

Self Cite

104

View full text Add to dashboard Cite

show abstract

“…Methods for measuring DNA adducts in humans have become more reliable in recent years, allowing detection of even background adduct levels in environmentally exposed individuals (16). PAH-DNA adduct levels reflect both exposure to PAH and possibly modulation of exposure by genetic factors, which affect carcinogen metabolism and DNA repair (15,(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in Nucleotide Excision Repair Genes, Polycyclic Aromatic Hydrocarbon-DNA Adducts, and Breast Cancer Risk

Crew

Gammon

Terry

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Genes involved in the nucleotide excision repair (NER) pathway, which removes bulky DNA adducts, are potential low-penetrance cancer susceptibility genes. We recently reported an association between detectable polycyclic aromatic hydrocarbon (PAH)-DNA adducts and breast cancer risk. Using a population-based breast cancer case-control study on Long Island, New York, we examined whether polymorphisms in NER genes modified the association between PAH-DNA adducts and breast cancer risk. We examined polymorphisms in ERCC1 (3 ¶-untranslated region 8092C/A), XPA (5 ¶-untranslated region À4G/A), XPD (Asp 312 Asn in exon 10), XPF (Arg 415 Gln in exon 8), and XPG (Asp 1104 His in exon 15) in 1,053 breast cancer cases and 1,102 population-based controls. The presence of at least one variant allele in XPD was associated with a 25% increase in the odds ratio [OR, 1.25; 95% confidence interval (95% CI), 1.04-1.50] for breast cancer. The increase associated with homozygosity of the variant alleles for XPD and ERCC1 was stronger among those with detectable PAH-DNA adduct levels (OR, 1.83; 95% CI, 1.22-2.76 and OR, 1.92; 95% CI, 1.14-3.25 for detectable versus nondetectable adducts and homozygous wild-type genotype for XPD and ERCC1, respectively). We found no association between XPA, XPF, and XPG genotypes, PAH-DNA adducts, and breast cancer risk. When we combined genotypes for these NER pathway genes, there was a significant trend for increasing breast cancer risk with increasing number of putative high-risk alleles. Overall, this study suggests that the risk of breast cancer may be elevated among women with polymorphisms in NER pathway genes and detectable PAH-DNA adducts. (Cancer Epidemiol Biomarkers Prev 2007;16(10):2033 -41)

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“…The immunoassay itself was plagued by issues of cross-reactivity of the antibody with other DNA alkylation adducts. However, measurement of the class of adducts as a whole, is still a useful marker [54]. The limited detection dynamics of the immunoassay made accurate adduct quantification impossible.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms of phase II xenobiotic-metabolizing and DNA repair genes and in vitro N-ethyl-N-nitrosourea-induced O6-ethylguanine levels in human lymphocytes

Jiao

Chang

Firozi

et al. 2007

Mutation Research/Genetic Toxicology and Environmental Mutagene

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This study tested the hypothesis that genetic variants of phase II detoxification enzymes and DNA repair proteins affect individual response to DNA damage from alkylating agents. In 171 healthy individuals, an immunoslot blot assay was used to measure O 6 -ethylguanosine (O 6 -EtGua) adduct levels in peripheral blood lymphocytes treated with N-ethyl-N-nitrosourea (ENU) in vitro. The genotypes of GSTM1, GSTT1, GSTP1 I 105 V and A 114 V, MGMT L 84 F and I 143 V, XPD D 312 N and K 751 Q, and XRCC3 T 241 M were determined. Demographic and exposure information was collected by in-person interview. Student's t test, analysis of (co)variance, and multiple linear regression models were used in statistical analyses. The mean and median (range) O 6 -EtGua levels were 94.6 and 84.8 (3.2-508.1) fmol/g DNA, respectively. The adduct level was significantly lower in people who smoked ≥ 25 years than that in never-smokers (square-root transformed mean values 8.20 versus 9.37, P = 0.03). Multiple linear regression models revealed that GSTT1 (β = −2.36, P = 0.009) polymorphism was a significant predictor of the level of adducts in 82 never-smokers, whereas the number of years smoked (β = −0.08, P = 0.005) and XRCC3 T 241 M (β = 2.22, P = 0.007) in 89 eversmokers. The association between GSTP1 I 105 V, MGMT I 143 V, and XPD D 312 N with the level of adducts was not conclusive. Each polymorphism could explain 2% to 10% of the variation of the adduct level. These observations suggest that GSTT1 null and XRCC3 T 241 M polymorphism may have some functional significance in modulating the level of ENU-induced DNA damage and these effects are smoking-dependent. Results from this exploratory study need to be confirmed in other experimental systems.

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Immunologic Methods for the Detection of Carcinogen Adducts in Humans

Cited by 66 publications

References 14 publications

Polycyclic aromatic hydrocarbon‐DNA adducts in liver tissues of hepatocellular carcinoma patients and controls

Polycyclic aromatic hydrocarbon‐DNA adducts in liver tissues of hepatocellular carcinoma patients and controls

Polymorphisms in Nucleotide Excision Repair Genes, Polycyclic Aromatic Hydrocarbon-DNA Adducts, and Breast Cancer Risk

Polymorphisms of phase II xenobiotic-metabolizing and DNA repair genes and in vitro N-ethyl-N-nitrosourea-induced O6-ethylguanine levels in human lymphocytes

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