Genetic modulation of ADH1B and ALDH2 polymorphisms with regard to alcohol and tobacco consumption for younger aged esophageal squamous cell carcinoma diagnosis Chien-Hung Lee 1,2 , Deng-Chyang Wu 2,3 , I-Chen Wu 3 , Yih-Gang Goan 4 , Jang-Ming Lee 5 , Shah-Hwa Chou 6 , Te-Fu Chan 2,7 , Hsiao-Ling Huang 8 , Yu-Hsiu Hung 9 , Meng-Chuan Huang 10 , Tai-Cheng Lai 1 , Tsu-Nai Wang 1,2 , Cheng-Che E. Lan 2,11 , Sharon Tsai 12 , Wen-Yi Lin 13 and Ming-Tsang Wu 2,9 * 1 Department of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan 2 Research Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 3 Department of Gastroenterology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 4 Department of Chest Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 5 Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan 6 Department of Chest Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 7 Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 8 Department of Oral Hygiene, Kaohsiung Medical University, Kaohsiung, Taiwan 9 Department of Family Medicine, Graduate Institute of Occupational Safety and Health, Kaohsiung Medical University, Kaohsiung, Taiwan 10 Department of Public Health and Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 11 Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 12 Department of Laboratory Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan 13 Department of Occupational Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan Genetic variants in alcohol dehydrogenase-1B (ADH1B) and alde- hyde dehydrogenase-2 (ALDH2) genes modulate acetaldehyde re- moval upon alcohol ingestion. Although these genetic vulnerabil- ities have been linked to higher esophageal squamous cell carci- noma (ESCC) risks, it is unclear whether they also determine the time of malignancy presentation. The purpose of this investigation was to unravel genotoxic effects of the two alcohol-metabolizing genes with regard to alcohol and tobacco consumption on the age at ESCC diagnosis and tumor dissemination. ADH1B/ALDH2 genotyping was performed on lymphocyte DNA specimens taken from 406 consecutively registered incident patients with pathol- ogy-proven ESCC. To fully utilize individual genetic and survival information, survival analyses and gene-longevity applied approaches were introduced. Among heavy drinkers, the ADH1B Arg/Arg (55 years) and ALDH2 Glu/Lys genotypes (54 years) were found to confer a 15 and 16 years earlier carcinoma diag- nosed age than His/His and Glu/Glu nondrinkers (both 70 years), respectively. For drinkers, 1-year age advancement was, sepa- rately, associated with a 0.977 and 0.953-fold stepwise reduced likelihood of being ADH1B Arg homozygote and ALDH2 Lys vari- ant. Noticeably elevated hazard-ratio (HR) for drinkers of ADH1B slow-form genotype and ALDH2 inactive-form allele were identified in smokers (HR 5 2.3–2.6), but no in nonsmokers. In smokers, appreciably higher cumulative cancer onset risks were correspondingly recognized from the age of 45 and 49 upward among any 1 Lys allele and Arg/Arg 1 Glu/Glu combined- ADH1B/ALDH2-genotype drinkers than nondrinkers. In conclu- sion, consumption of tobacco and alcohol, coupled with genetic susceptibilities associated with acetaldehyde elimination, as modu- lated by ADH1B and ALDH2 genotypes, determines a substantial magnitude of tumorigenetic effect on earlier age ESCC diagnosis. ' 2009 UICC Key words: age factor; alcohol drinking; alcohol dehydrogenase; aldehyde dehydrogenase; areca; esophageal neoplasms; smoking Carcinoma stemming from the esophagus ranks as the eighth most common cancer in the world and is one of the deadliest and, yet, most neglected forms of cancer. 1 Given the insidious nature of this neoplasm, it has been found that more than 50% of the eventual patients already have unresectable and/or metastatic con- ditions at the time of tumor presentation. 2 Although recent advan- ces in the diagnosis, staging and treatment of esophageal cancer have brought about noteworthy improvement toward some manner of survival, 75% of the patients still die within 1 year of diagnosis, and currently just 5–14% of such patients survive at least 5 years. 2,3 Due, in part, to the high case fatality rate, younger esoph- ageal carcinoma onset has been linked to a shorter life expectancy. This leads to a number of challenging health-related issues for the respective family, as well as to substantial work productivity losses for the country. Alcohol intake is a well-recognized determinant for squamous cell carcinoma (SCC) of the esophagus, accounting for over 60% of this type of malignancy in the United States, 4 Japan 5 and Tai- wan. 6,7 Although the biological mechanisms underlying alcohol- induced carcinogenesis have not been defined fully, DNA damage by carcinogenic acetaldehyde (the pivotal metabolite of ethanol) is one of the powerful events for the development of upper aerodi- gestive tract (UADT) neoplasms. 8,9 In an experimental study, a 7- folds higher level of acetaldehyde-DNA adduct has been detected in heavy alcohol drinkers than in controls. 10 Alcohol metabolism involves two steps of enzymatic oxidation. Upon consumption of an alcoholic beverage, ethanol is first cata- lytically oxidized into acetaldehyde, occurring mainly through alcohol dehydrogenase-1B (ADH1B). It is subsequently metabo- lized into harmless acetate, chiefly by aldehyde dehydrogenase-2 (ALDH2). 11 A single-point variant in the ADH1B gene, resulting in amino acid substitution in the encoded enzymes from arginine (Arg) to histidine (His) at codon 48 (Arg48His), bestows the ‘‘fast’’ metabolistic character on ethanol. 12 About a 40-times greater maximum velocity (V max ) has been identified for the ADH1B fast His allele than that for the less active Arg/Arg form. 11,13 In contrast, a single nucleotide transition in the ALDH2 Grant sponsor: The Taiwan National Science Council; Grant numbers: NSC 95-2314-B-037-081 and 95-2314-B-039-042-MY3, Grant sponsor: the Taiwan National Health Research Institutes; Grant numbers: NHRI- CN-IN-9007P and NHRI-EX94-9428PI; Grant sponsor: Intramural Grants from Kaohsiung Medical University Hospital; Grant number: KMUH 96- 6G01, 96-6G02, 96-6G03 and 96-6G04; Grant sponsor: KMU Research Center of Excellence for Environmental Medicine; Grant number: KMU- EM-97-1.1ab. *Correspondence to: Department of Family Medicine, Graduate Insti- tute of Occupational Safety and Health, Kaohsiung Medical University, No. 100 Shih-Chuan 1st Road, Kaohsiung 807, Taiwan. Fax: 1886-7-322-1806. E-mail: 960021@ms.kmuh.org.tw Received 19 November 2008; Accepted after revision 23 January 2009 DOI 10.1002/ijc.24357 Published online 17 February 2009 in Wiley InterScience (www.interscience. wiley.com). Int. J. Cancer: 125, 1134–1142 (2009) ' 2009 UICC Publication of the International Union Against Cancer