CEBP CTRC-AACR San Antonio Breast Cancer Symposium 2008 Conference on Cancer Prevention - Washington, D.C.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lawson, K. A.
Right arrow Articles by Albanes, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lawson, K. A.
Right arrow Articles by Albanes, D.
Cancer Epidemiology Biomarkers & Prevention Vol. 14, 2275-2276, September 2005
© 2005 American Association for Cancer Research

Null Results in Brief

Association of the NAD(P)H:Quinone Oxidoreductase (NQO1) 609C->T Polymorphism with Lung Cancer Risk among Male Smokers

Karla A. Lawson1,2, Karen Woodson3, Jarmo Virtamo4 and Demetrius Albanes2

1 Division of Cancer Prevention, National Cancer Institute, NIH/Department of Health and Human Services, Bethesda, Maryland; 2 Division of Cancer Epidemiology and Genetics and 3 Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; and 4 Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland

Requests for reprints: Karla Lawson, Nutritional Epidemiology Branch, 6120 Executive Boulevard, EPS Suite 320, Room 3032, Bethesda, MD 20852. Phone: 301-594-6545; Fax: 301-496-6829. E-mail: lawsonka{at}mail.nih.gov


   Introduction
Top
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
NAD(P)H:quinone oxidoreductase (NQO1, DT-diaphorase) is an enzyme involved in both the detoxification and activation of a variety of substrates (1). This obligate two-electron reductase has chemoprotective properties including reduction of quinone to hydroquinone forms (1, 2), allowing avoidance of semiquinone free radical production and subsequent oxidative damage, as well as metabolism of vitamin E, catalyzing the production of a vitamin E antioxidant metabolite, vitamin E hydroquinone (3). Conversely, NQO1 is also involved in bioactivation of procarcinogens such as nitroaromatic compounds and heterocyclic amines (1, 4). A base pair change in the NQO1 gene (NQO1*2) results in a proline to serine substitution in the encoded protein, causing the production of a variant protein with only 2% enzymatic activity of the wild-type that is quickly degraded, leaving a lack of detectable protein in those homozygous for the NQO1*2 variant (5-7). Reports on the association between this NQO1 polymorphism and lung cancer risk are mixed (8-20), although most show increased risk associated with the wild-type (9-11, 15, 16, 20) or show a null association (12, 14, 17, 19). We examined the association between the NQO1 polymorphism and lung cancer risk in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study and assessed any interaction with vitamin E supplementation.


   Materials and Methods
Top
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
We conducted a nested case-control study within the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study cohort of male smokers in Finland. The trial was a randomized, placebo-controlled primary prevention trial investigating the efficacy of supplemental {alpha}-tocopherol (50 mg/d) and ß-carotene (20 mg/d) in reducing the incidence of lung and other cancers. The original cohort, recruited between 1985 and 1988, consisted of 29,133 men, ages 50 to 69 years, who reported smoking at least five cigarettes per day. Study design and main outcomes have been reported previously, as have main trial results (21, 22). Cases and controls for the current study were chosen based on availability of a whole blood sample collected during the study. Genotype data were obtained on 353 individuals with incident lung cancer (ICD9-162) diagnosed through July 2001. Cases were identified by the Finnish Cancer Registry and the Register of Causes of Death, and histologic information was available for 345 cases (58 adenocarcinoma, 59 small cell, 157 squamous cell, 56 other, and 15 unknown). Genotype data were also obtained on 360 control subjects. Medical, habitual diet, smoking information, and a fasting blood sample (stored at –70°C) were collected at baseline. DNA was isolated from a whole blood sample collected during follow-up, as previously described (23). PCR was used to amplify DNA using 5'-TCC TCA GAG TGG CAT TCT GC-3' and 5'-TCT CCT CAT CCT GTA CCT CT-3' primers. Restriction enzyme digestion was used to assess variant status, as the NQO1*2 (T) minor allele introduces a Hinf1 restriction cut site. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression with adjustment for age at randomization, cigarettes smoked per day, years smoked, and intervention assignment ({alpha}-tocopherol versus no {alpha}-tocopherol, ß-carotene versus no ß-carotene). Those heterozygous or homozygous for the minor allele were combined in the analysis, as NQO1 levels are diminished for both genotypes depending on presence of the allele (6) and due to the fact that only 3.7% of the sample was homozygous for the minor allele. Effect modification was assessed using cross-product interaction terms in the above model and by stratified analyses. The study had 90% power ({alpha} = 0.05) to detect an OR of at least 1.6 for wild-type (CC) versus having one or two copies of the minor allele (CT + TT), as seen in previous studies (9, 10, 16). Statistical analysis was done using STATA 8.0 (Stata Inc., College Station, TX).


   Results
Top
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The NQO1 genotypes were in Hardy-Weinberg equilibrium and the allele frequency of the variant (T) was 0.18. Cases and controls did not differ in any characteristics analyzed, except for those related to smoking status. Cases reported a longer lifetime duration of smoking and more cigarettes smoked per day.

The NQO1 CC genotype was not associated with risk of lung cancer after adjustment for age, number of cigarettes smoked per day, duration of smoking, and intervention assignment (Table 1). There was no association between genotype and advanced disease (tumor-node-metastasis cancer stage III-IV: OR, 1.03; 95% CI, 0.71-1.50; n = 206 cases) or nonadvanced disease (tumor-node-metastasis stage I-II: OR, 1.14; 95% CI, 0.73-1.78; n = 136 cases). In addition, no relationship was seen between genotype and histology-specific lung cancer (Table 1). Neither trial intervention assignment, baseline serum vitamin E level, smoking, age at randomization, age at diagnosis, alcohol intake, nor dietary {alpha}-tocopherol, vitamin C, or flavonoid intake had effect on the relationship between NQO1 and lung cancer risk.


View this table:
[in this window]
[in a new window]
  		Table 1. OR and 95% CIs for lung cancer and histology-specific lung cancer by NQO1 genotype

 

   Discussion
Top
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The functional NQO1 polymorphism was not related to lung cancer risk in this population of male smokers, despite having a substantial number of cases compared with previous studies and adequate statistical power to test the hypothesis. Although some studies reported a positive association between the NQO1*2 minor allele and lung cancer risk (8, 13, 18), most studies have shown a significant (9, 10, 15, 16, 20) or statistically nonsignificant (11) positive association for the NQO1 common allele. Our results are consistent with four studies showing no association between the polymorphism and lung cancer risk (12, 14, 17, 19).

We failed to substantiate the role of smoking in the relationship between the NQO1 polymorphism and lung cancer risk, and found no effect modification by antioxidant status as assessed by baseline serum vitamin E concentrations, dietary antioxidants, or randomized supplementation with {alpha}-tocopherol or ß-carotene, an interaction we had hypothesized a priori. The lack of effect modification by smoking status could be due to limited variability in smoking exposure in this population, as all participants in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study were smokers. The association for NQO1 was also not modified by age at diagnosis, as seen by Bock et al. (20), possibly due to enrollment having been restricted to men of ages 50 to 69 years at baseline, with median age at diagnosis of 66 years. Finally, no association was seen between genotype and specific histologies such as seen for small-cell carcinoma (13), squamous cell carcinoma (14, 18), or adenocarcinoma (11, 16, 17) in previous studies.


   Footnotes
 
Grant support: USPHS contracts N01-CN-45165, N01-RC-45035, and N01-RC-37004 from the National Cancer Institute, NIH, Department of Health and Human Services.

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.

Received 5/24/05; accepted 6/20/05.


   References
Top
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Ross D, Kepa JK, Winski SL, Beall HD, Anwar A, Siegel D. NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms. Chem Biol Interact 2000;129:77–97.[CrossRef][Medline]
  2. Nebert DW, Roe AL, Vandale SE, Bingham E, Oakley GG. NAD(P)H:quinone oxidoreductase (NQO1) polymorphism, exposure to benzene, and predisposition to disease: a HuGE review. Genet Med 2002;4:62–70.[Medline]
  3. Siegel D, Bolton EM, Burr JA, Liebler DC, Ross D. The reduction of {alpha}-tocopherolquinone by human NAD(P)H:quinone oxidoreductase: the role of {alpha}-tocopherolhydroquinone as a cellular antioxidant. Mol Pharmacol 1997;52:300–5.[Abstract/Free Full Text]
  4. De Flora S, Bennicelli C, D'Agostini F, Izzotti A, Camoirano A. Cytosolic activation of aromatic and heterocyclic amines. Inhibition by dicoumarol and enhancement in viral hepatitis B. Environ Health Perspect 1994;102 Suppl 6:69–74.
  5. Traver RD, Siegel D, Beall HD, et al. Characterization of a polymorphism in NAD(P)H:quinone oxidoreductase (DT-diaphorase). Br J Cancer 1997;75:69–75.[Medline]
  6. Siegel D, McGuinness SM, Winski SL, Ross D. Genotype-phenotype relationships in studies of a polymorphism in NAD(P)H:quinone oxidoreductase 1. Pharmacogenetics 1999;9:113–21.[Medline]
  7. Siegel D, Anwar A, Winski SL, Kepa JK, Zolman KL, Ross D. Rapid polyubiquitination and proteasomal degradation of a mutant form of NAD(P)H:quinone oxidoreductase 1. Mol Pharmacol 2001;59:263–8.[Abstract/Free Full Text]
  8. Rosvold EA, McGlynn KA, Lustbader ED, Buetow KH. Identification of an NAD(P)H:quinone oxidoreductase polymorphism and its association with lung cancer and smoking. Pharmacogenetics 1995;5:199–206.[Medline]
  9. Wiencke JK, Spitz MR, McMillan A, Kelsey KT. Lung cancer in Mexican-Americans and African-Americans is associated with the wild-type genotype of the NAD(P)H:quinone oxidoreductase polymorphism. Cancer Epidemiol Biomarkers Prev 1997;6:87–92.[Abstract]
  10. Chen H, Lum A, Seifried A, Wilkens LR, Le Marchand L. Association of the NAD(P)H:quinone oxidoreductase 609C->T polymorphism with a decreased lung cancer risk. Cancer Res 1999;59:3045–8.[Abstract/Free Full Text]
  11. Lin P, Wang HJ, Lee H, et al. NAD(P)H:quinone oxidoreductase polymorphism and lung cancer in Taiwan. J Toxicol Environ Health A 1999;58:187–97.[CrossRef][Medline]
  12. Yin L, Pu Y, Liu TY, Tung YH, Chen KW, Lin P. Genetic polymorphisms of NAD(P)H quinone oxidoreductase, CYP1A1 and microsomal epoxide hydrolase and lung cancer risk in Nanjing, China. Lung Cancer 2001;33:133–41.[CrossRef][Medline]
  13. Lewis SJ, Cherry NM, Niven RM, Barber PV, Povey AC. Polymorphisms in the NAD(P)H:quinone oxidoreductase gene and small cell lung cancer risk in a UK population. Lung Cancer 2001;34:177–83.[CrossRef][Medline]
  14. Xu LL, Wain JC, Miller DP, et al. The NAD(P)H:quinone oxidoreductase 1 gene polymorphism and lung cancer: differential susceptibility based on smoking behavior. Cancer Epidemiol Biomarkers Prev 2001;10:303–9.[Abstract/Free Full Text]
  15. Hamajima N, Matsuo K, Iwata H, et al. NAD(P)H:quinone oxidoreductase 1 (NQO1) C609T polymorphism and the risk of eight cancers for Japanese. Int J Clin Oncol 2002;7:103–8.[Medline]
  16. Sunaga N, Kohno T, Yanagitani N, et al. Contribution of the NQO1 and GSTT1 polymorphisms to lung adenocarcinoma susceptibility. Cancer Epidemiol Biomarkers Prev 2002;11:730–8.[Abstract/Free Full Text]
  17. Lin P, Hsueh YM, Ko JL, Liang YF, Tsai KJ, Chen CY. Analysis of NQO1, GSTP1, and MnSOD genetic polymorphisms on lung cancer risk in Taiwan. Lung Cancer 2003;40:123–9.[CrossRef][Medline]
  18. Alexandrie AK, Nyberg F, Warholm M, Rannug A. Influence of CYP1A1, GSTM1, GSTT1, and NQO1 genotypes and cumulative smoking dose on lung cancer risk in a Swedish population. Cancer Epidemiol Biomarkers Prev 2004;13:908–14.[Abstract/Free Full Text]
  19. Lan Q, Mumford JL, Shen M, et al. Oxidative damage-related genes AKR1C3 and OGG1 modulate risks for lung cancer due to exposure to PAH-rich coal combustion emissions. Carcinogenesis 2004;25:2177–81.[Abstract/Free Full Text]
  20. Bock CH, Wenzlaff AS, Cote ML, Land SJ, Schwartz AG. NQO1 T allele associated with decreased risk of later age at diagnosis lung cancer among never smokers: results from a population-based study. Carcinogenesis 2005;26:381–6.[Abstract/Free Full Text]
  21. The ATBC Cancer Prevention Study Group. The {alpha}-Tocopherol, ß-Carotene Lung Cancer Prevention Study: design, methods, participant characteristics, and compliance. Ann Epidemiol 1994;4:1–10.[Medline]
  22. The {alpha}-Tocopherol, ß Carotene Cancer Prevention Study Group. The effect of vitamin E and ß carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029–35.[Abstract/Free Full Text]
  23. Woodson K, Ratnasinghe D, Bhat NK, et al. Prevalence of disease-related DNA polymorphisms among participants in a large cancer prevention trial. Eur J Cancer Prev 1999;8:441–7.[Medline]



This article has been cited by other articles:


Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
C. Chao, Z.-F. Zhang, J. Berthiller, P. Boffetta, and M. Hashibe
NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Pro187Ser Polymorphism and the Risk of Lung, Bladder, and Colorectal Cancers: a Meta-analysis.
Cancer Epidemiol. Biomarkers Prev., May 1, 2006; 15(5): 979 - 987.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lawson, K. A.
Right arrow Articles by Albanes, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lawson, K. A.
Right arrow Articles by Albanes, D.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online