Alcohol consumption and bladder cancer risk with or without the flushing response: The Japan Public Health Center‐based Prospective Study

Abstract

The association between alcohol consumption and bladder cancer risk has been insufficiently investigated in East Asian populations, who frequently have the inactive enzyme for metabolizing acetaldehyde. Given that acetaldehyde associated with alcohol consumption is assessed as a carcinogen, consideration of differences in acetaldehyde exposure would aid accuracy in assessing the bladder cancer risk associated with alcohol consumption. Here, we conducted a population-based cohort study in Japan to examine this association, including information on the flushing response as a surrogate marker of the capacity of acetaldehyde metabolism. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariate Cox proportional hazard models. During follow up from 1990 through 2012 for the 95,915 subjects (45,649 men and 50,266 women, aged 40-69 years), 354 men and 110 women were newly diagnosed with bladder cancer. No significant association between alcohol consumption and bladder cancer risk was observed in the overall analysis. Among male flushers, HRs were 1.04 (95% CI 0.70-1.54), 1.67 (1.16-2.42), 1.02 (0.62-1.67) and 0.63 (0.33-1.20) for alcohol consumption of 1-150, 151-300, 301-450, >450 g/week of pure ethanol compared with non-drinkers and occasional drinkers, respectively, indicating an inverted U-shaped association between alcohol consumption and bladder cancer risk. In contrast, no significant association was identified among male non-flushers. The marginally significant interaction between alcohol consumption and the flushing response (p for interaction = 0.083) may support our hypothesis that acetaldehyde derived from alcohol consumption is associated with bladder cancer risk. A prospective study considering polymorphisms of genes involved in acetaldehyde metabolism is warranted.

Light to moderate amount of lifetime alcohol consumption and risk of cancer in Japan

“…Acetaldehyde is carcinogenic via multiple mechanisms (eg, stimulating cell proliferation and inducing DNA damage) and increases cancer risk even with light levels of lifetime alcohol consumption, regardless of race or region of the world . In the current study, even light to moderate levels of lifetime alcohol consumption appeared to increase most of the upper aerodigestive and gastrointestinal cancers . In contrast to the patterns observed in Western settings, we observed no protective effects of light to moderate lifetime alcohol consumption for colorectal and kidney cancers.…”

“…For upper aerodigestive and gastrointestinal cancers, our observed patterns would be plausible because of the common genetic vulnerability to acetaldehyde in the Japanese . Acetaldehyde is carcinogenic via multiple mechanisms (eg, stimulating cell proliferation and inducing DNA damage) and increases cancer risk even with light levels of lifetime alcohol consumption, regardless of race or region of the world . In the current study, even light to moderate levels of lifetime alcohol consumption appeared to increase most of the upper aerodigestive and gastrointestinal cancers .…”

“…Second, because of the limitation of our data set, we could not assess alcohol‐related cancer risk by different types of alcoholic beverages (eg, Japanese sake, beer, wine, and whiskey). However, studies suggest that the ethanol (but not the other components of alcoholic beverages) matters primarily for cancer risk, regardless of the types of alcoholic beverages . In addition, we could not assess other explanatory variables such as menopausal hormone therapy (for female breast cancer), a family history of cancer, diet (eg, coffee and red meat), physical activities, and ALDH2 genotypes .…”

“…Recent studies have raised concerns about the risk of even light to moderate levels of alcohol consumption for cancer incidence . In Japan as well as East Asian countries, previous studies regarding alcohol‐related cancer risk are widely available for various cancer sites . For example, in the Japan Public Health Center (JPHC)–based prospective study, the potential risk of light to moderate levels of alcohol consumption was implied to some extent with the use of trend analysis .…”

“…For example, alcohol use increases circulating sex hormone levels, and this contributes to excess breast cancer risk . In addition, acetaldehyde, a metabolite of ethanol classified as a group 1 carcinogen by the International Agency for Research on Cancer, stimulates cell proliferation and induces DNA damage . The Japanese have a higher prevalence of polymorphisms in the aldehyde dehydrogenase 2 (ALDH2) enzyme, which makes them slower at metabolizing acetaldehyde .…”