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Cancer Research 67, 5628, June 15, 2007. doi: 10.1158/0008-5472.CAN-07-0983
© 2007 American Association for Cancer Research
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In vitro Benzo[a]pyrene Diol Epoxide–Induced DNA Adducts and Risk of Squamous Cell Carcinoma of Head and Neck

Donghui Li1, Li-E Wang2, Ping Chang1, Adel K. El-Naggar3, Erich M. Sturgis2,4 and Qingyi Wei2

Departments of 1 Gastrointestinal Medical Oncology, 2 Epidemiology, 3 Pathology, and 4 Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Qingyi Wei, Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Unit 1365, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3020; Fax: 713-563-0999; E-mail: qwei{at}mdanderson.org.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In this large confirmatory study of 803 patients with squamous cell carcinoma of head and neck (SCCHN) and 839 controls frequency matched by age, sex, and ethnicity, we further examined potential predictors of benzo[a]pyrene diol epoxide (BPDE)-induced adduct levels and their associations with SCCHN risk. BPDE-DNA adduct levels were determined by the 32P-postlabeling method in peripheral lymphocytes after in vitro challenged by BPDE. We also genotyped for GSTM1 null, GSTT1 null, GSTP1 Ile105Val, and GSTP1 Ala114Val. Potential predictors of BPDE-DNA adducts were evaluated by stratification and multivariate linear regression analyses and the association between adduct levels and SCCHN risk by multivariate logistic regression analyses. We found that mean BPDE-DNA adduct levels (the relative adduct labeling x 107 ± SD) were significantly higher in cases (77.6 ± 111.8) than in controls (57.3 ± 98.3; P < 0.001). Using the median control value (29.22) as a cutoff, 63% of the cases were distributed above this level (adjusted odds ratio, 1.71; 95% confidence interval, 1.39–2.10). A significant dose-response relationship was observed between adduct quartiles and SCCHN risk (Ptrend < 0.001). Multivariate linear regression analysis revealed that ethnicity and smoking were significant predictors of BPDE-DNA adduct levels in controls. In conclusion, we confirmed the previously reported association between in vitro BPDE-induced DNA adduct levels and SCCHN risk, and the assay may help identify individuals at high risk of developing smoking-related cancers. [Cancer Res 2007;67(12):5628–34]


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Cigarette smoking and alcohol consumption play a major role in the etiology of squamous cell carcinoma of the head and neck (SCCHN; ref. 1). However, not every smoker or drinker develops SCCHN, suggesting that individual susceptibility to tobacco carcinogens may also play a role in the etiology (2). Accumulating evidence does suggest an association between SCCHN risk and individual sensitivity to carcinogens as determined by genetic variation in carcinogen metabolism and DNA repair (2). Although genotypic biomarkers for carcinogen activation, detoxification, and DNA repair have been used extensively to characterize genetic susceptibility to carcinogenesis (3), their functional relevance has not been well established.

As a phenotypic marker for biological effects, the levels of in vivo DNA adducts reflect not only the levels of exposure but also the individual's variation in response to such exposure (4). Because the levels of in vivo DNA adducts depend on the dose and duration of exposure that are often poorly estimated, we developed the in vitro carcinogen-induced adduct assay that can be measured under the same exposure conditions in terms of dose and time. Indeed, in a pilot case-control study, we assayed benzo[a]pyrene diol epoxide (BPDE)-induced DNA adduct levels in cultured peripheral lymphocytes and found that such induced adduct levels may be a risk factor for SCCHN (5). The present large, independent, and confirmatory study validated the published preliminary results and further evaluated the effects of tobacco smoke, alcohol consumption, and genotypes of three phase II conjugation genes on the levels of in vitro BPDE-induced adducts.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study population. Recruitment of case and control subjects for this study has been described elsewhere (6). In brief, of all patients with newly diagnosed, untreated SCCHN that had been histopathologically confirmed at The University of Texas M. D. Anderson Cancer Center between January 2000 and March 2006, ~95% of eligible patients we approached participated in this study. The control subjects were recruited from among healthy visitors to the outpatient clinics at M. D. Anderson Cancer Center who were accompanying cancer patients and who were genetically unrelated to any of the case subjects or to each other. Approximately 90% of eligible control subjects we approached participated in this study. Control subjects were frequency matched with the cases in terms of age (±5 years), sex, and ethnicity. After informed consent was obtained, each subject completed a questionnaire and donated a blood sample for doing the in vitro–induced adduct assays. The study protocol was approved by M. D. Anderson institutional review board.

Cell culture and BPDE treatment. Experimental cells were cultured and treated with BPDE as described previously (5). Briefly, 1 mL whole blood from each subject was cultured in each of two T-25 flasks (each flask containing 9 mL of standard RPMI 1640 supplemented with 15% fetal bovine serum and 112.5 µg/mL phytohemagglutinin) with phytohemagglutinin to stimulate DNA repair activity (7, 8). After 67 h of phytohemagglutinin stimulation, BPDE was added to the culture at a final concentration of 4 µmol/L, and the cells were harvested after another 5-h incubation for doing the assay (5, 9).

Genotyping. The genotypes of GSTM1 null, GSTT1 null, GSTP1 Ile105Val, and GSTP1 Ala114Val were analyzed by PCR and restriction digestion using published primers and a modification of previously published methods (10, 11). PCR analyses were done in a PTC-200 DNA Engine Peltier thermal cycler (MJ Research) using 10 µL of the PCR mixture.

Statistical analysis. The {chi}2 test was used to compare differences in the distributions of categorical data, and Student's t tests, ANOVA, and multiple linear regression analyses were used to compare the differences in continuous variables. The induced BPDE-DNA adducts were quantified by the relative adduct labeling (RAL) x 107 and normalized by natural logarithmic transformation. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated by unconditional logistic regression analysis with and without adjustment for other covariates. Both median and quartile adduct levels in the control subjects were used as cutoff values. Interaction terms of the covariates were generated by using the product of any two variables and assessed in the unconditional multivariate logistic regression models. The tests for additive interactions were done using Stata software (version 9.0; StataCorp LP) and all other statistical tests were done using Statistical Analysis System software (version 9.1.3; SAS Institute). All statistical analyses were two sided.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The final analysis included 803 patients with cancers of the oral cavity (237 of 803, 29.5%), pharynx (414 of 803, 51.6%; including 375 oropharynx and 39 hypopharynx), or larynx (152 of 803, 18.9%) and 839 controls. Although the cases and controls were well frequency matched by age, sex, and ethnicity, the cases had a higher mean age (±SD; 56.3 ± 11.2) than the controls (55.0 ± 11.8; P = 0.014). The cases were significantly more likely than the controls to be current smokers (38.3% versus 16.4%; P < 0.001) and current drinkers (50.8% versus 38.7%; P < 0.001; Table 1 ).


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  		Table 1. Distribution of select variables and GST genotypes

 
The Hardy-Weinberg equilibrium (HWE) was not applicable to the GSTM1 and GSTT1 genotypes, but only the distribution of the GSTP1 Ala114Val genotype significantly deviated from the HWE among the cases ({chi}2 = 5.67; P < 0.05). Although none of the genotype distributions was different between the cases and controls (Table 1), 63% of the cases (508 of 803) had the untransformed RAL values greater than the control median cutoff of 29.2/107, and the difference was associated with 1.71-fold increased SCCHN risk (95% CI, 1.39–2.10; adjusted for age, sex, smoking status, drinking status, and GST genotypes in a logistic regression model; Table 1).

Both the mean and median RAL levels were significantly higher in the cases (77.6 ± 111.8; median, 44.0) than in the controls (57.3 ± 98.3; median, 29.2; P < 0.001 for both comparisons; Table 2 ), and further, natural logarithmic transformation of the RAL values did not change the magnitude of difference (3.59 ± 1.43 versus 3.12 ± 1.56; P < 0.0001). Further stratification revealed that differences in the mean transformed RAL values between the cases and controls remained in the vast majority of the strata, except for groups of age 61 to 70, Hispanic and African Americans, current smokers, and GSTP1 haplotype Val105_Ala114 (Table 2). Among the controls, the trend test for the adduct levels was significant for non-Hispanic white<African American<Hispanic American (P = 0.018, ANOVA) and for never<former<current smokers (P = 0.014, ANOVA). Among the cases, only the difference between GSTP1_105 genotypes was significant (P = 0.035) with lower adduct levels (mean, 3.53) in carriers of the GSTP1 Ile/Val+Val/Val variant genotype than that in carriers of the Ile/Ile homozygous genotype (mean, 3.68; Table 2). There was also ethnic difference in the distributions of GST genotypes among the controls (P = 0.004 for GSTP1_105 genotypes and P = 0.013 for GSTP1_114 genotypes). For example, the frequency of GSTP1_105 Ile/Val+Val/Val genotypes was 42.0% for non-Hispanic whites but 30.8 for Hispanics, whereas the frequency of GSTP1_114 Ala/Val+Val/Val genotypes was 14.7% for non-Hispanic whites but 1.6% for African Americans (data not shown). Further stratification and analysis by smoking status and genotypes for non-Hispanic whites only suggested that the GST genotypes modulated the levels of induced BPDE-DNA adducts (Table 3 ). For example, among control current smokers (n = 121), carriers of the GSTM1-null genotype had significantly higher adduct levels (mean, 3.69) than carriers of the GSTM1 wild-type genotype (mean, 3.14; P = 0.033), whereas among control never smokers, carriers of the GSTP1_105 Ile/Val+Val/Val of GSTP1_114 Ala/Val+Val/Val genotypes had significantly lower adduct levels than carriers of the GSTP1_105 Ile/Ile (P = 0.017) or GSTP1_114 Ala/Ala genotypes (P = 0.040), but these differences were not observed among the cases (Table 3).


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  		Table 2. Subgroup comparisons of the levels of BPDE-induced DNA adducts in SCCHN cases and controls

 

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  		Table 3. Genotype effects on BPDE-induced DNA adducts among non-Hispanic whites by smoking status

 
In logistic regression analyses, a per-unit increase in natural log-transformed RAL x 107 values was associated with a >20% increase in SCCHN risk (adjusted OR, 1.22; 95% CI, 1.14–1.31; Table 4 ). When the quartiles of BPDE-induced DNA adduct values for control subjects were used as cutoff points, a significant dose-response relationship was observed between increasing adduct levels and increasing risk of SCCHN (P < 0.0001, trend test; Table 4). When the risk estimates were further stratified by these variables (Table 4), the trend toward increasing risk of SCCHN as adduct levels increased remained significant for all strata except for minority group (i.e., African Americans and Hispanics) that had much fewer numbers included in the analysis. We did not find evidence of any interactions between the BPDE adduct levels and other variables in this study.


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  		Table 4. Logistic regression analysis of BPDE-induced DNA adducts and stratification by ethnicity, smoking status, and GST genotypes in cases and controls

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this large phenotypic case-control study, which did not include any of the subjects described in our previously reported pilot study (5), with phenotypic and genotypic assays being done in separate laboratories and the data being decoded only for final analyses, we have confirmed our previous observation that high levels of in vitro BPDE-induced DNA adducts in cultured lymphocytes are associated with a significantly increased SCCHN risk. Although ethnicity, cigarette smoking, and possible genetic variations in carcinogen detoxification may modulate these adduct levels, increased levels of BPDE-induced DNA adducts, a combined measure of host cell detoxification and DNA repair capacity, is an independent risk factor for SCCHN. Because the ubiquitous carcinogen benzo[a]pyrene is present in cigarette smoke and the ambient environment, cellular sensitivity to in vitro BPDE challenge may thus have practical implications for the assessment of tobacco-related cancer risk in humans.

The in vitro BPDE-induced DNA adduct assay likely measures the combined effects of carcinogen detoxification and DNA repair on the induced adduct levels. Glutathione S-transferases (GST) catalyze the conjugation of reduced glutathione and electrophilic compounds, including tobacco carcinogens such as BPDE (12). Of the eight families of soluble GSTs with overlapping substrate specificities in humans (13), GSTM1, GSTT1, and GSTP have been extensively studied for their associations with cancer susceptibility (14, 15). Homozygous deletion (null genotype) of GSTM1 and GSTT1 has been associated with the loss of enzyme activity and increased sensitivity to cytogenetic damage. Of the combinations of the GSTP1 Ile105Val and Ala114Val polymorphisms, including GSTP1*A (Ile105_Ala114), GSTP1*B (Val105_Ala114), and GSTP1*C (Val105_Val114) allele, the GSTP1*B and GSTP1*C alleles have a higher conjugation activity toward BPDE than the GSTP1*A allele (16). Indeed, our study also showed that controls carrying either the GSTP1*B or GSTP1*C allele had significantly lower adduct levels than controls carrying the GSTP1*A allele. These phenotypic and genotypic associations provide evidence of a possible mechanism underlying associations between GST genotypes and altered risk of smoking-related cancer.

In the controls, the highest levels of in vitro BPDE-induced DNA adducts in current smokers followed by former smokers and never smokers we observed are consistent with the previous observation that smokers are significantly more sensitive to genotoxic challenges and thus have more DNA or chromosome damage than never smokers (17). Although smoking itself may have caused the formation of adducts in lymphocytic DNA, the in vivo smoking-induced DNA adduct levels were usually 100 to 1,000 times lower than the in vitro induced adduct levels observed in our previous (5) and current studies. Furthermore, we analyzed the only known BPDE-DNA adducts, and smoking status was adjusted in the multivariate logistic regression analysis in the present study. Therefore, our finding of an independent effect of the in vitro–induced adducts on SCCHN risk is unlikely biased by smoking status.

In our study population, current smokers seemed to have experienced a compensatory increase in DNA repair capacity in response to a constant level of smoking-induced DNA damage (18), but they may also have experienced reduced levels of glutathione or GST enzymes in response to the constant presence to tobacco carcinogens, and the genetically impaired GST activity may further predispose these individuals to BPDE-induced DNA damage. However, these subtle effects of GST polymorphisms on BPDE-induced DNA adduct levels can only be detected when controlling for other factors in large studies. Our observed effect of GSTM1 and GSTP1 genotypes, but not GSTT1, on the BPDE-induced DNA adduct levels is biologically plausible because GSTT1 has little conjugation activity toward BPDE (19).

Ethnicity seemed to influence the adduct levels with unknown mechanisms. Among our controls, we observed a significantly higher level of BPDE-induced adducts in African Americans and Hispanics than in non-Hispanic whites. The higher adduct levels in Hispanics were possibly due to a lower frequency of GSTP1 variant genotypes, although the number of Hispanics in this study was relatively small. Therefore, the ethnic difference in DNA repair capacity and sensitivity to carcinogen exposure needs further investigation. We did not detect any significant difference in BPDE-induced adduct levels by alcohol status, but it is likely that alcohol consumption may exert its carcinogenic effects through DNA damage, increased oxidative stress, and altered folate metabolism (20).

Overall, the significant dose-response relationship between in vitro BPDE-induced DNA adduct levels and SCCHN risk reported here, as in our previous pilot study (5), further shows the strength and validity of this assay. However, the results in some subgroup analyses may have been by chance and should be validated in larger studies. Nevertheless, this assay alone may not provide a complete risk profile and thus should be considered part of a battery of complementary assays needed for cancer risk assessment.


   Acknowledgments
 
Grant support: NIH grant ES 11740 (Q. Wei).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We thank Margaret Lung, Leanel Fairly, and Kathryn Patterson for their assistance in recruiting the subjects; Ping Xiong, Zhaozheng Guo, Yawei Qiao, Jianzhong He, and Kejin Xu for their laboratory assistance; Monica Domingue for manuscript preparation; and Jude Richard, ELS, for scientific editing.

Received 3/15/07. Revised 4/19/07. Accepted 5/ 3/07.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
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