Alcohol-Induced DNA Injury in Esophageal Squamous Cell Carcinoma

  • Masashi Tamaoki
  • Yusuke Amanuma
  • Shinya Ohashi
  • Manabu MutoEmail author


Alcohol consumption is a major risk factor for esophageal squamous cell carcinoma. Acetaldehyde, a highly reactive compound that causes various types of DNA damage, plays a central role in alcohol-induced esophageal carcinogenesis. Acetaldehyde is mainly generated from the metabolism of ethanol by alcohol dehydrogenase 1B and is then detoxified to acetic acid by aldehyde dehydrogenase 2 (ALDH2). Alcohol consumption increases blood, saliva, and breath acetaldehyde levels, especially in individuals with inactive ALDH2 that are strongly associated with the risk of squamous cell carcinoma in the esophagus. In this chapter, we review recent studies of alcohol-mediated carcinogenesis in the squamous epithelium of the esophagus, focusing especially on acetaldehyde-induced DNA damage.


Acetaldehyde DNA damage DNA adduct 


  1. 1.
    Torre LA, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRefGoogle Scholar
  2. 2.
    Pennathur A, et al. Oesophageal carcinoma. Lancet. 2013;381:400–12.CrossRefGoogle Scholar
  3. 3.
    Pickens A, et al. Geographical distribution and racial disparity in esophageal cancer. Ann Thorac Surg. 2003;76:S1367–9.CrossRefGoogle Scholar
  4. 4.
    Bosetti C, et al. Trends in oesophageal cancer incidence and mortality in Europe. Int J Cancer. 2008;122:1118–29.CrossRefGoogle Scholar
  5. 5.
    Seitz HK, et al. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer. 2007;7:599–612.CrossRefGoogle Scholar
  6. 6.
    Brooks PJ, et al. Acetaldehyde and the genome: beyond nuclear DNA adducts and carcinogenesis. Environ Mol Mutagen. 2014;55:77–91.CrossRefGoogle Scholar
  7. 7.
    Ohashi S, et al. Recent advances from basic and clinical studies of esophageal squamous cell carcinoma. Gastroenterology. 2015;149:1700–15.CrossRefGoogle Scholar
  8. 8.
    Peng GS, et al. Effect of the allelic variants of aldehyde dehydrogenase ALDH2*2 and alcohol dehydrogenase ADH1B*2 on blood acetaldehyde concentrations. Hum Genomics. 2009;3:121–7.CrossRefGoogle Scholar
  9. 9.
    Neumark YD, et al. Alcohol dehydrogenase polymorphisms influence alcohol-elimination rates in a male Jewish population. Alcohol Clin Exp Res. 2004;28:10–4.CrossRefGoogle Scholar
  10. 10.
    Zhang L, et al. Gene—environment interactions on the risk of esophageal cancer among Asian populations with the G48A polymorphism in the alcohol dehydrogenase-2 gene: a meta-analysis. Tumour Biol. 2014;35:4705–17.CrossRefGoogle Scholar
  11. 11.
    Zhang Y, et al. Alcohol dehydrogenase-1B Arg47His polymorphism is associated with head and neck cancer risk in Asian: a meta-analysis. Tumour Biol. 2015;36:1023–7.CrossRefGoogle Scholar
  12. 12.
    Treutlein J, et al. ADH1B Arg48His allele frequency map: filling in the gap for Central Europe. Biol Psychiatry. 2014;75:e15.CrossRefGoogle Scholar
  13. 13.
    Enomoto N, Takase S, Yasuhara M, et al. Acetaldehyde metabolism in different aldehyde dehydrogenase-2 genotypes. Alcohol Clin Exp Res. 1991;15:141–4.CrossRefGoogle Scholar
  14. 14.
    Yokoyama A, et al. Genetic polymorphisms of alcohol dehydrogense-1B and aldehyde dehydrogenase-2, alcohol flushing, mean corpuscular volume, and aerodigestive tract neoplasia in Japanese drinkers. Adv Exp Med Biol. 2015;815:265–79.CrossRefGoogle Scholar
  15. 15.
    Goedde HW, et al. Distribution of ADH2 and ALDH2 genotypes in different populations. Hum Genet. 1992;88:344–6.CrossRefGoogle Scholar
  16. 16.
    Harada S, et al. Aldehyde dehydrogenase deficiency as cause of facial flushing reaction to alcohol in Japanese. Lancet (Lond Engl). 1981;2:982.CrossRefGoogle Scholar
  17. 17.
    Matsuo K, et al. Gene–environment interaction between an aldehyde dehydrogenase-2 (ALDH2) polymorphism and alcohol consumption for the risk of esophageal cancer. Carcinogenesis. 2001;22:913–6.CrossRefGoogle Scholar
  18. 18.
    Yang SJ, et al. Relationship between genetic polymorphisms of ALDH2 and ADH1B and esophageal cancer risk: a meta-analysis. World J Gastroenterol. 2010;16:4210–20.CrossRefGoogle Scholar
  19. 19.
    Boccia S, et al. Aldehyde dehydrogenase 2 and head and neck cancer: a meta-analysis implementing a Mendelian randomization approach. Cancer Epidemiol Biomark Prev. 2009;18:248–54.CrossRefGoogle Scholar
  20. 20.
    Yokoyama A, et al. Alcohol and aldehyde dehydrogenase gene polymorphisms and oropharyngolaryngeal, esophageal and stomach cancers in Japanese alcoholics. Carcinogenesis. 2001;22:433–9.CrossRefGoogle Scholar
  21. 21.
    Chang J, et al. Genomic analysis of oesophageal squamous-cell carcinoma identifies alcohol drinking-related mutation signature and genomic alterations. Nat Commun. 2017;8:15290.CrossRefGoogle Scholar
  22. 22.
    Homann N, et al. High acetaldehyde levels in saliva after ethanol consumption: methodological aspects and pathogenetic implications. Carcinogenesis. 1997;18:1739–43.CrossRefGoogle Scholar
  23. 23.
    Muto M, et al. Acetaldehyde production by non-pathogenic Neisseria in human oral microflora: implications for carcinogenesis in upper aerodigestive tract. Int J Cancer. 2000;88:342–50.CrossRefGoogle Scholar
  24. 24.
    Uebelacker M, et al. Quantitative determination of acetaldehyde in foods using automated digestion with simulated gastric fluid followed by headspace gas chromatography. J Autom Methods Manag Chem. 2011;2011:907317.CrossRefGoogle Scholar
  25. 25.
    Lachenmeier DW, et al. The role of acetaldehyde outside ethanol metabolism in the carcinogenicity of alcoholic beverages: evidence from a large chemical survey. Food Chem Toxicol. 2008;46:2903–11.CrossRefGoogle Scholar
  26. 26.
    Salaspuro VJ, et al. Eliminating carcinogenic acetaldehyde by cysteine from saliva during smoking. Cancer Epidemiol Biomark Prev. 2006;15:146–9.CrossRefGoogle Scholar
  27. 27.
    Linderborg K, et al. Potential mechanism for calvados-related oesophageal cancer. Food Chem Toxicol. 2008;46:476–9.CrossRefGoogle Scholar
  28. 28.
    Secretan B, et al. A review of human carcinogens—part E: tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol. 2009;10:1033–4.CrossRefGoogle Scholar
  29. 29.
    Slaughter DP, et al. Field cancerization in oral stratified squamous epithelium, clinical implications of multicentric origin. Cancer. 1953;6:963–8.CrossRefGoogle Scholar
  30. 30.
    Mori M, et al. Lugol staining pattern and histology of esophageal lesions. Am J Gastroenterol. 1993;88:701–5.PubMedGoogle Scholar
  31. 31.
    Muto M, et al. Association of multiple Lugol-voiding lesions with synchronous and metachronous esophageal squamous cell carcinoma in patients with head and neck cancer. Gastrointest Endosc. 2002;56:517–21.CrossRefGoogle Scholar
  32. 32.
    Katada C, et al. Alcohol consumption and multiple dysplastic lesions increase risk of squamous cell carcinoma in the esophagus, head, and neck. Gastroenterology. 2016;151:860–9.CrossRefGoogle Scholar
  33. 33.
    Muto M, et al. Association between aldehyde dehydrogenase gene polymorphisms and the phenomenon of field cancerization in patients with head and neck cancer. Carcinogenesis. 2002;23:1759–65.CrossRefGoogle Scholar
  34. 34.
    Yokoyama A, et al. Polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 and the blood and salivary ethanol and acetaldehyde concentrations of Japanese alcoholic men. Alcohol Clin Exp Res. 2010;34:1246–56.CrossRefGoogle Scholar
  35. 35.
    Yokoyama A, et al. Salivary acetaldehyde concentration according to alcoholic beverage consumed and aldehyde dehydrogenase-2 genotype. Alcohol Clin Exp Res. 2008;32:1607–14.CrossRefGoogle Scholar
  36. 36.
    Nieminen MT, et al. Local acetaldehyde: an essential role in alcohol-related upper gastrointestinal tract carcinogenesis. Cancers (Basel). 2018;10:pii: E11.CrossRefGoogle Scholar
  37. 37.
    Dong YJ, et al. Expression and activities of class IV alcohol dehydrogenase and class III aldehyde dehydrogenase in human mouth. Alcohol. 1996;13:257–62.CrossRefGoogle Scholar
  38. 38.
    Bik EM, et al. Bacterial diversity in the oral cavity of 10 healthy individuals. ISME J. 2010;4:962–74.CrossRefGoogle Scholar
  39. 39.
    Kurkivuori J, et al. Acetaldehyde production from ethanol by oral streptococci. Oral Oncol. 2007;43:181–6.CrossRefGoogle Scholar
  40. 40.
    Nieminen MT, et al. Acetaldehyde production from ethanol and glucose by non-Candida albicans yeasts in vitro. Oral Oncol. 2009;45:e245–8.CrossRefGoogle Scholar
  41. 41.
    Uittamo J, et al. Chronic candidosis and oral cancer in APECED patients: production of carcinogenic acetaldehyde from glucose and ethanol by Candida albicans. Int J Cancer. 2009;124:754–6.CrossRefGoogle Scholar
  42. 42.
    Vakevainen S, et al. High salivary acetaldehyde after a moderate dose of alcohol in ALDH2-deficient subjects: strong evidence for the local carcinogenic action of acetaldehyde. Alcohol Clin Exp Res. 2000;24:873–7.CrossRefGoogle Scholar
  43. 43.
    Mizumoto A, et al. Molecular mechanisms of acetaldehyde-mediated carcinogenesis in squamous epithelium. Int J Mol Sci. 2017;18:E1943.CrossRefGoogle Scholar
  44. 44.
    Wang M, et al. Identification of DNA adducts of acetaldehyde. Chem Res Toxicol. 2000;13:1149–57.CrossRefGoogle Scholar
  45. 45.
    Fang JL, et al. Development of a 32P-postlabelling method for the analysis of adducts arising through the reaction of acetaldehyde with 2′-deoxyguanosine-3′-monophosphate and DNA. Carcinogenesis. 1995;16:2177–85.CrossRefGoogle Scholar
  46. 46.
    Hecht SS, et al. New DNA adducts of crotonaldehyde and acetaldehyde. Toxicology. 2001;166:31–6.CrossRefGoogle Scholar
  47. 47.
    Matsuda T, et al. Increased formation of hepatic N2-ethylidene-2′-deoxyguanosine DNA adducts in aldehyde dehydrogenase 2-knockout mice treated with ethanol. Carcinogenesis. 2007;28:2363–6.CrossRefGoogle Scholar
  48. 48.
    Balbo S, et al. Kinetics of DNA adduct formation in the oral cavity after drinking alcohol. Cancer Epidemiol Biomark Prev. 2012;21:601–8.CrossRefGoogle Scholar
  49. 49.
    Balbo S, et al. N2-ethyldeoxyguanosine as a potential biomarker for assessing effects of alcohol consumption on DNA. Cancer Epidemiol Biomark Prev. 2008;17:3026–32.CrossRefGoogle Scholar
  50. 50.
    Yukawa Y, et al. Combination of ADH1B*2/ALDH2*2 polymorphisms alters acetaldehyde-derived DNA damage in the blood of Japanese alcoholics. Cancer Sci. 2012;103:1651–5.CrossRefGoogle Scholar
  51. 51.
    Balbo S, et al. Increased levels of the acetaldehyde-derived DNA adduct N2-ethyldeoxyguanosine in oral mucosa DNA from rhesus monkeys exposed to alcohol. Mutagenesis. 2016;31:553–8.CrossRefGoogle Scholar
  52. 52.
    Amanuma Y, et al. Protective role of ALDH2 against acetaldehyde-derived DNA damage in oesophageal squamous epithelium. Sci Rep. 2015;5:14142.CrossRefGoogle Scholar
  53. 53.
    Matsuda T, et al. Effective utilization of N2-ethyl-20-deoxyguanosine triphosphate during DNA synthesis catalyzed by mammalian replicative DNA polymerases. Biochemistry. 1999;38:929–35.CrossRefGoogle Scholar
  54. 54.
    Upton DC, et al. Replication of N2-ethyldeoxyguanosine DNA adducts in the human embryonic kidney cell line 293. Chem Res Toxicol. 2006;19:960–7.CrossRefGoogle Scholar
  55. 55.
    Garcia CC, et al. [13C2]-acetaldehyde promotes unequivocal formation of 1,N2-propano-2′-deoxyguanosine in human cells. J Am Chem Soc. 2011;133:9140–3.CrossRefGoogle Scholar
  56. 56.
    Matsuda T, et al. Increased DNA damage in ALDH2-deficient alcoholics. Chem Res Toxicol. 2006;19:1374–8.CrossRefGoogle Scholar
  57. 57.
    Mao H, et al. Duplex DNA catalyzes the chemical rearrangement of a malondialdehyde deoxyguanosine adduct. Proc Natl Acad Sci U S A. 1999;96:6615–20.CrossRefGoogle Scholar
  58. 58.
    Minko IG, et al. Chemistry and biology of DNA containing 1,N2-deoxyguanosine adducts of the, unsaturated aldehydes acrolein, crotonaldehyde, and 4-hydroxynonenal. Chem Res Toxicol. 2009;22:759–78.CrossRefGoogle Scholar
  59. 59.
    Brooks PJ, et al. DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis. Alcohol. 2005;35:187–93.CrossRefGoogle Scholar
  60. 60.
    Matsuda T, et al. Specific tandem GG to TT base substitutions induced by acetaldehyde are due to intra-strand crosslinks between adjacent guanine bases. Nucleic Acids Res. 1998;26:1769–74.CrossRefGoogle Scholar
  61. 61.
    Cho YJ, et al. Stereospecific formation of interstrand carbinolamine DNA cross-links by crotonaldehyde- and acetaldehyde-derived -CH3-OH-1,N2-propano-2′-deoxyguanosine adducts in the 50-CpG-30 sequence. Chem Res Toxicol. 2006;19:195–208.CrossRefGoogle Scholar
  62. 62.
    Loureiro AP, et al. Trans,trans-2,4-decadienal-induced 1,N2-etheno-20-deoxyguanosine adduct formation. Chem Res Toxicol. 2000;13:601–9.CrossRefGoogle Scholar
  63. 63.
    Tanaka K, et al. ALDH2 modulates autophagy flux to regulate acetaldehyde-mediated toxicity thresholds. Am J Cancer Res. 2016;6:781–96.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Akasaka S, et al. Mutagenicity of site-specifically located 1,N2-ethenoguanine in Chinese hamster ovary cell chromosomal DNA. Chem Res Toxicol. 1999;12:501–7.CrossRefGoogle Scholar
  65. 65.
    Jansson T. The frequency of sister chromatid exchanges in human lymphocytes treated with ethanol and acetaldehyde. Hereditas. 1982;97:301–3.CrossRefGoogle Scholar
  66. 66.
    Paget V, et al. Acetaldehyde-induced mutational pattern in the tumour suppressor gene tp53 analysed by use of a functional assay, the FASAY (functional analysis of separated alleles in yeast). Mutat Res. 2008;652:12–9.CrossRefGoogle Scholar
  67. 67.
    Lin DC, et al. Genomic and molecular characterization of esophageal squamous cell carcinoma. Nat Genet. 2014;46:467–73.CrossRefGoogle Scholar
  68. 68.
    Sawada G, et al. Genomic landscape of esophageal squamous cell carcinoma in a Japanese population. Gastroenterology. 2016;150:1171–82.CrossRefGoogle Scholar
  69. 69.
    Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517:576–82.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Masashi Tamaoki
    • 1
  • Yusuke Amanuma
    • 1
  • Shinya Ohashi
    • 1
  • Manabu Muto
    • 1
    Email author
  1. 1.Department of Therapeutic Oncology, Graduate School of MedicineKyoto UniversityKyotoJapan

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