Abstract
NAD(P)H:quinone oxidoreductase 1 (NQO1) is a cytosolic flavoprotein that catalyzes the two-electron reduction of quinoid compounds into hydroquinones, thus protecting cells from oxidative damage. A single base substitution (C→T) polymorphism at 609 in the NQO1 gene reduces quinone reductase activity. Thus, the lack of enzymatic activity in the homozygous C609T NQO1 polymorphism (rs1800566) may play a pivotal role in tumor development. We hypothesized that a genetic variant in NQO1 may modify individual susceptibility to hepatocellular carcinoma (HCC). To test this hypothesis that the variant may play a role in HCC susceptibility, we conducted a hospital-based case–control study of 476 HCC patients and 526 cancer-free controls in a Chinese population. The matrix-assisted laser desorption/ionization time-of-flight mass spectrometry method was performed to detect the polymorphism. The results showed that the variant alleles and genotypes of NQO1 C609T were more common among cases than those among controls (P = 0.003 and P = 0.024). Compared with the NQO1 609CC genotype, there was a significantly greater risk of HCC associated with the variant NQO1 609TT [adjusted odds ratio (OR) = 1.60, 95 % confidence interval (CI) = 1.12–2.28] and combined NQO1 609TC/TT (adjusted OR = 1.37, 95 % CI = 1.04–1.80) genotypes. Moreover, when subgroup analyses were performed, we found that the increase in risk was more evident among younger subjects, men, HbsAg-positive individuals, never smokers, never drinkers, and subjects without family history of cancer. These results suggest that the presence of the NQO1 C609T polymorphism may be a marker of genetic susceptibility to HCC.
Similar content being viewed by others
Abbreviations
- NQO1:
-
NAD(P)H:quinone oxidoreductase 1
- HCC:
-
Hepatocellular carcinoma
- HBV:
-
Hepatitis B virus
- OR:
-
Odds ratio
- CI:
-
Confidence interval
- SNP:
-
Single nucleotide polymorphisms
- HWE:
-
Hardy–Weinberg equilibrium
References
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.
Farazi PA, Depinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev. 2006;6:674–87.
Yuen MF, Hou JL, Chutaputti A. Hepatocellular carcinoma in the Asia pacific region. J Gastroenterol Hepatol. 2009;24:346–53.
Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol. 2001;2:533–43.
Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology. 2008;48:2047–63.
Chen CJ, Chen DS. Interaction of hepatitis B virus, chemical carcinogen, and genetic susceptibility: multistage hepatocarcinogenesis with multifactorial etiology. Hepatology. 2002;36:1046–9.
Nissen NN, Martin P. Hepatocellular carcinoma: the high-risk patient. J Clin Gastroenterol. 2002;35(5 Suppl2):S79–85.
Bowen DG, Walker CM. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature. 2005;436:946–52.
Kato N, Ji G, Wang Y, et al. Large-scale search of single nucleotide polymorphisms for hepatocellular carcinoma susceptibility genes in patients with hepatitis C. Hepatology. 2005;42:846–53.
Kim YJ, Lee HS. Single nucleotide polymorphisms associated with hepatocellular carcinoma in patients with chronic hepatitis B virus infection. Intervirology. 2005;48:10–5.
Joseph P, Long DJ, Klein-Szanto AJ, Jaiswal AK. Role of NAD(P)H:quinone oxidoreductase 1 (DT diaphorase) in protection against quinone toxicity. Biochem Pharmacol. 2000;60:207–14.
Iskander K, Jaiswal AK. Quinone oxidoreductases in protection against myelogenous hyperplasia and benzene toxicity. Chem Biol Interact. 2005;153–154:147–57.
Siegel D, Gustafson DL, Dehn DL, et al. NAD(P)H:quinone oxidoreductase 1: role as a superoxide scavenger. Mol Pharmacol. 2004;65:1238–47.
Dinkova-Kostova AT, Talalay P. NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector. Arch Biochem Biophys. 2010;501:116–23.
Asher G, Tsvetkov P, Kahana C, Shaul Y. A mechanism of ubiquitin-independent proteasomal degradation of the tumor suppressors p53 and p73. Genes Dev. 2005;19:316–21.
Asher G, Lotem J, Kama R, Sachs L, Shaul Y. NQO1 stabilizes p53 through a distinct pathway. Proc Natl Acad Sci U S A. 2002;99:3099–104.
Asher G, Lotem J, Sachs L, Kahana C, Shaul Y. Mdm-2 and ubiquitin-independent p53 proteasomal degradation regulated by NQO1. Proc Natl Acad Sci U S A. 2002;99:13125–30.
Nioi P, Hayes JD. Contribution of NAD(P)H:quinone oxidoreductase 1 to protection against carcinogenesis, and regulation of its gene by the Nrf2 basic-region leucine zipper and the arylhydrocarbon receptor basic helix-loop-helix transcription factors. Mutat Res. 2004;555:149–71.
Rauth AM, Goldberg Z, Misra V. DT-diaphorase: possible roles in cancer chemotherapy and carcinogenesis. Oncol Res. 1997;9:339–49.
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.
Traver RD, Siegel D, Beall HD, et al. Characterization of a polymorphism in NAD(P)H: quinone oxidoreductase (DT-diaphorase). Br J Cancer. 1997;5:69–75.
Siegel D, McGuinness SM, Winski, et al. Genotype-phenotype relationships in studies of a polymorphism in NAD(P)H:quinone oxidoreductase 1. Pharmacogenetics. 1999;9:113–21.
Misra V, Grondin A, Klamut HJ, et al. Assessment of the relationship between genotypic status of a DT-diaphorase point mutation and enzymatic activity. Br J Cancer. 2000;83:998–1002.
Kuehl BL, Paterson JW, Peacock JW, et al. Presence of a heterozygous substitution and its relationship to DT-diaphorase activity. Br J Cancer. 1995;72:555–61.
Zhang JH, Li Y, Wang R, et al. NQO1 C609T polymorphism associated with esophageal cancer and gastric cardiac carcinoma in North China. World J Gastroenterol. 2003;9:1390–3.
van der Logt EM, Bergevoet SM, Roelofs HM, et al. Role of epoxide hydrolase, NAD(P)H:quinone oxidoreductase, cytochrome P450 2E1 or alcohol dehydrogenase genotypes in susceptibility to colon cancer. Mutat Res. 2006;593:39–49.
Menzel HJ, Sarmanova J, Soucek P, et al. Association of NQO1 polymorphism with spontaneous breast cancer in two independent populations. Br J Cancer. 2004;90:1989–94.
Schulz WA, Krummeck A, Rosinger I, et al. Increased frequency of a null-allele for NAD(P)H:quinone oxidoreductase in patients with urological malignancies. Pharmacogenetics. 1997;7:235–9.
Long 2nd DJ, Waikel RL, Wang XJ, et al. NAD(P)H:quinone oxidoreductase 1 deficiency increases susceptibility to benzo(a)pyrene-induced mouse skin carcinogenesis. Cancer Res. 2000;60:5913–5.
Long 2nd DJ, Waikel RL, Wang XJ, Roop DR, Jaiswal AK. NAD(P)H:quinone oxidoreductase 1 deficiency and increased susceptibility to 7,12-dimethylbenz[a]-anthracene-induced carcinogenesis in mouse skin. J Natl Cancer Inst. 2001;93:1166–70.
Akkiz H, Bayram S, Bekar A, et al. No association of NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T polymorphism and risk of hepatocellular carcinoma development in Turkish subjects. Asian Pac J Cancer Prev. 2010;11:1051–8.
Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6:674–87.
El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.
Nebert DW, Roe AL, Vandale SE, et al. NAD(P)H:quinone oxidoreductase (NQO1) polymorphism, exposure to benzene, and predisposition to disease: a HuGE review. Genet Med. 2002;4:62–70.
Iizuka N, Oka M, Yamada-Okabe H, et al. Comparison of gene expression profiles between hepatitis Bvirus- and hepatitis C virus-infected hepatocellular carcinoma by oligonucleotide microarray data on the basis of a supervised learning method. Cancer Res. 2002;62:3939–44.
Asher G, Lotem J, Cohen B, et al. Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxidoreductase 1. Proc Natl Acad Sci U S A. 2001;98:1188–93.
Gong X, Kole L, Iskander K, et al. NRH:quinone oxidoreductase 2 and NAD(P)H:quinone oxidoreductase 1 protect tumor suppressor p53 against 20s proteasomal degradation leading to stabilization and activation of p53. Cancer Res. 2007;67:5380–8.
Long 2nd DJ, Gaikwad A, Multani A, et al. Disruption of the NAD(P)H:quinone oxidoreductase 1 (NQO1) gene in mice causes myelogenous hyperplasia. Cancer Res. 2002;62:3030–6.
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.
Begleiter A, Norman A, Leitao D, et al. Role of NQO1 polymorphisms as risk factors for squamous cell carcinoma of the head and neck. Oral Oncol. 2005;41:927–33.
Soucek P, Sarmanova J, Kristensen VN, et al. Genetic polymorphisms of biotransformation enzymes in patients with Hodgkin’s and non-Hodgkin’s lymphomas. Int Arch Occup Environ Health. 2002;75:S86–92.
Kiyohara C, Yoshimasu K, Takayama K, et al. NQO1, MPO, and the risk of lung cancer: a HuGE review. Genet Med. 2005;7:463–78.
Sarbia M, Bitzer M, Siegel D, et al. Association between NAD(P)H: quinoneoxidoreductase 1 (NQO1) inactivating C609T polymorphism and adenocarcinoma of the upper gastrointestinal tract. Int J Cancer. 2003;107:381–6.
Liu Y, Zhang D. The NQO1 C609T polymorphism and risk of lung cancer: a meta-analysis. Asian Pac J Cancer Prev. 2011;12:3091–5.
Wang Z, Hu J, Zhong J. Meta-analysis of the NAD(P)H: quinine oxidoreductase 1 gene 609 C>T polymorphism with esophageal cancer risk. DNA Cell Biol. 2012;31:560–7.
Wang X, Zhang X, Qiu B, et al. MDM2 SNP309T>G polymorphism increases susceptibility to hepatitis B virus-related hepatocellular carcinoma in a northeast Han Chinese population. Liver Int. 2012;32:1172–8.
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China (no. 81172372 and no. 30901720) and Ph.D. Programs Foundation of Ministry of Education of China (no. 20090181120111).
Conflicts of interest
None
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Liu, F., Luo, L., Wei, Y. et al. A functional NQO1 609C>T polymorphism and risk of hepatocellular carcinoma in a Chinese population. Tumor Biol. 34, 47–53 (2013). https://doi.org/10.1007/s13277-012-0509-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-012-0509-x