ArticleAlcohol and the risk of colon and rectal cancer with mutations in the K-ras gene
Introduction
Consumption of alcohol is well-known to be associated with several malignant and nonmalignant diseases. Although alcohol itself is not carcinogenic, there is increasing evidence that acetaldehyde, a cytotoxic, mutagenic, and carcinogenic metabolite of alcohol, rather than alcohol itself, is responsible for tumor enhancing effects (Salaspuro, 2003, Seitz et al., 2001). Acetaldehyde can bind to cellular proteins and DNA, and the additional formation of stable DNA adducts could trigger replication errors and mutations in tumor suppressor genes or oncogenes. Acetaldehyde may also interfere with DNA repair by inhibiting enzymes important to the repair of adducts caused by alkylating agents (Ahmed, 1995, Salaspuro, 2003, Seitz et al., 2001). Regarding these mechanisms, it is plausible to consider alcohol consumption as a possible risk factor for developing colorectal cancer (CRC).
Development of CRC is a multistep process, characterized by an accumulation of several genetic alterations driving normal colorectal mucosa to transform into highly malignant derivatives (Fearon and Vogelstein, 1990, Vogelstein et al., 1988). An early event in colorectal tumorigenesis is often an activating mutation in the K-ras oncogene. K-ras mutations occur in 30–60% of colorectal carcinomas and are involved in the progression of small adenomas to the more clinically relevant larger adenomas. Therefore, K-ras mutations may be an important contributor to CRC development. Most K-ras mutations are G → A transitions and G → T transversions (Brink et al., 2003, Fearon and Vogelstein, 1990). Several studies have shown that patients with these types of K-ras point mutations have a poor prognosis and a high risk of recurrence of the disease (Cerottini et al., 1998, Span et al., 1996). Knowledge of the etiology of K-ras mutations arising in colorectal tumors may provide valuable clues for prevention strategies.
The association between alcohol consumption and CRC was long debated, and according to a recently published pooled analysis of eight prospective cohort studies, CRC risk is only increased when daily alcohol consumption levels exceed 30.0 g (Cho et al., 2004). This suggests that there may be a threshold in alcohol consumption above which the risk of CRC is increased. The role of different types of alcoholic beverages on the risk of CRC is less clear, although beer consumption has more consistently been implicated in the etiology of rectal cancer. In the past, beer in the Netherlands and in other European countries was contaminated with relatively large amounts of N-nitrosodimethylamine (NDMA) (mean 1.2 μg/kg) (Spiegelhalder et al., 1979, Stephany and Schuller, 1980). As such, beer drinking accounted for 90% of the NDMA intake in beer drinkers, whose total NDMA intake was as much as 10 times higher than that of nonbeer drinkers. Jacoby et al. (1992) have shown that nitrosamines have mutagenic properties and are able to induce mutations, especially G → A transitions in the K-ras gene in rodents. However, since 1979, changes in the beer-brewing process have greatly decreased the NDMA contaminations in beers (Ellen & Schuller, 1983). Yet it is likely that the adverse effects of NDMA still influences the risk of (rectal) cancer for up to 10 years later, and that this declines in the years thereafter.
Taking into account the mutagenic and carcinogenic potentials of acetaldehyde mentioned above, we hypothesized that alcohol consumption is associated with an increased risk of mutations in the K-ras oncogene involved in CRC. Hence, we examined the associations between consumption of alcohol and various alcoholic beverages and the risk of colon and rectal cancer with and without K-ras gene mutations. In a second hypothesis, we stated that beer consumption is associated with G → A mutations in the K-ras gene involved in CRC. To answer this hypothesis, we examined the associations between beer consumption and this specific type of K-ras mutation among the colon and rectal cancer cases in our study population.
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Study population
In September 1986, the Netherlands Cohort Study on diet and cancer was initiated. The study design has been described in detail elsewhere (Van den Brandt et al., 1990a). Briefly, the cohort included 58,279 men and 62,573 women, aged 55–69 years at baseline and originating from 204 municipal population registries throughout the country. All cohort members completed an extensive self-administered questionnaire on daily dietary habits during the year preceding the start of the study, lifestyle
Results
Alcohol intake and baseline characteristics of the study population are presented in Table 1. Overall, both male and female colon and rectal cancer patients tended to be older in age than subcohort members. For female colon cancer cases, cases with a K-ras+ tumor were older in age than cases with a K-ras− tumor (P < .05). Furthermore, for both men and women, there were no significant differences in alcohol consumption or lifestyle characteristics when comparing the K-ras− colon tumors with the
Alcohol, CRC, and K-ras gene mutations
In the current prospective study, we have investigated associations between alcohol consumption and the risk of colon and rectal cancer with and without K-ras mutations, as our hypothesis implied a relationship between alcohol consumption and colorectal tumors harboring a K-ras mutation. When considering all male plus female colorectal tumors according to K-ras mutational status, our results showed that a daily alcohol consumption of 30.0 g/day and more was associated with an increased risk of
Acknowledgments
Financial support for this study is provided by a grant from the European Research Advisory Board.
We are indebted to the participants of this study and further wish to thank the regional cancer registries (IKA, IKL, IKMN, IKN, IKO, IKR, IKST, IKW, IKZ, and VIKC), and the Netherlands nationwide registry of pathology. We also thank Dr. A. Volovics and Dr. A. Kester for statistical advice; Dr A. de Bruïne for pathological advise; Dr. M. Brink for the collection of tissue samples; financial support
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