Effect of alcohol consumption, cigarette smoking and flushing response on esophageal cancer risk: A population-based cohort study (JPHC study)
Introduction
Esophageal cancer is the sixth most common cause of cancer death among men both worldwide and in Japan [1]. The risk of esophageal cancer and its histology is varied widely among geographic areas [2]. In China, Japan and other East Asia countries, for example, more than 90% of cases are squamous cell carcinoma, while adenocarcinoma is more common in the United States and European countries [3], [4]. A positive association between alcohol use, cigarette smoking, and the risk of esophageal squamous cell carcinoma (ESCC) has been well established in many case-control and cohort studies [5], [6], [7], [8].
Ethanol is eliminated from the body via oxidation, first to acetaldehyde and then to acetate. Although most of the acetaldehyde generated during alcohol metabolism is promptly eliminated by aldehyde dehydrogenase-2 (ALDH2), concentrations following alcohol consumption become elevated in individuals with inactive ALDH2. An inactive allele of ALDH2 encoded by the gene ALDH2∗1/2∗2 is prevalent in Japanese [9], [10], with a frequency of 0.28 [11] versus less than 0.03 in Caucasians [12]. Individuals with inactive ALDH2 who drink alcohol exhibit the flushing response, which includes facial flushing, palpitations, drowsiness and other unpleasant symptoms caused by acetaldehydemia [13]. Previous reports have noted that regular flushing might predict the possession of inactive ALDH2, whereas infrequent or absent flushing is associated with active ALDH2 [14], [15].
Acetaldehyde is recognized as a highly toxic, mutagenic and carcinogenic agent [16]. Several case-control studies have demonstrated that inactive ALDH2 is a strong risk factor for ESCC among drinkers [10], [17], [18], [19]. The flushing response, regarded as a surrogate marker of ALDH2, may also be associated with risk of ESCC. Although one case-control study showed an association between flushing response and the risk of ESCC among alcohol drinkers [20], this association has not been investigated in a prospective cohort study.
Here, we examined the effect of alcohol consumption, cigarette smoking and flushing response on the risk of ESCC in a large-scale population-based cohort study.
Section snippets
Study population
The Japan Public Health Center-based Prospective Study on Cancer and Cardiovascular Disease (JPHC study) started in 1990 for the first group (cohort I) and in 1993 for the second (cohort II). The study design is described in detail elsewhere [21]. Briefly, cohort I covered five areas administered by Public Health Centers (PHC) in five prefectures (Iwate, Akita, Nagano, Okinawa, and Tokyo), and cohort II included six PHC areas in six prefectures (Ibaraki, Niigata, Kochi, Nagasaki, Okinawa, and
Results
Baseline characteristics by flushing response and alcohol consumption are listed in Table 1. There was a high prevalence of regular drinkers among subjects without a flushing response (non-flushers) in both cohorts. The percentage of subjects with a flushing response (flushers) decreased as the level of regular weekly alcohol consumption increased. Smoking status did not differ between flushers and non-flushers. A high prevalence of current smokers was found among regular drinkers. Intake
Discussion
Consistent with previous studies, this prospective population-based study demonstrated that alcohol consumption and cigarette smoking are strongly associated with the incidence of ESCC in Japanese men. Although no significant effect modification was observed between flushing response and alcohol consumption among light or non-smokers, strong effect modification was detected in heavy smokers. These data suggest that heavy alcohol consumption together with heavy smoking may increase the risk of
Conflicts of interest
None declared.
Acknowledgements
This work was supported by a Grant-in-Aid for Cancer Research and for the Third Term Comprehensive Control Research for Cancer from the Ministry of Health, Labour and Welfare of Japan.
Members of the JPHC Study Group (principal investigator: S. Tsugane): S. Tsugane, M. Inoue, T. Sobue, and T. Hanaoka, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo; J. Ogata, S. Baba, T. Mannami, and A. Okayama, National Cardiovascular Center, Suita; K. Miyakawa, F. Saito, A.
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Study group members are listed in the Acknowledgment.