Alcohol and the risk of colon and rectal cancer with mutations in the K-ras gene

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The first metabolite of alcohol, acetaldehyde, may trigger replication errors and mutations in DNA, which may predispose to developing
colorectal cancer (CRC). In a prospective study on colon and rectal cancer, we investigated the following hypotheses: alcohol consumption
is associated with an increased risk of mutations in the K-ras oncogene, and beer consumption is associated with an increased risk of G/
A mutations in this gene. Therefore, we studied the associations between consumption of alcohol and alcoholic beverages and the risk of
CRC without and with specific K-ras gene mutations. In 1986, 120,852 men and women, aged 55e69 years, completed a questionnaire on
risk factors for cancer. The caseecohort approach was used for data processing and analyses. After 7.3 years of follow-up, excluding the
first 2.3 years, complete data from 4,076 subcohort members, 428 colon and 150 rectal cancer patients, were available for data analyses.
Incidence rate ratios (RRs) and corresponding 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards models.
Compared to abstaining, a total alcohol consumption of 30.0 g/day and more was associated with the risk of colon and rectal cancer with
and without a K-ras mutation in both men and women. Independent from alcohol intake, liquor consumption when compared to nonliquor
consumption was associated with an increased risk of rectal cancer with a wild type K-ras in men (RR: 2.25, 95% CI: 1.0e5.0). Beer consumption
was not clearly associated with the risk of colon and rectal tumors harboring G/A mutations in the K-ras gene in men. This
association could not be assessed in women because of sparse beer consumption. In conclusion, alcohol does not seem to be involved in
predisposing to CRC through mutations in the K-ras gene, and specifically beer consumption is not associated with colon and rectal tumors
harboring a G/A mutation. 2006 Elsevier Inc. All rights reserved.

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Alcohol and the risk of colon and rectal cancer with
mutations in the K-ras gene
Brenda W.C. Bongaertsa,*, Anton F.P.M. de Goeijb, Piet A. van den Brandta,
Matty P. Weijenberga
aNutrition and Toxicology Research Institute Maastricht (NUTRIM), Department of Epidemiology,
University Maastricht, P.O. Box 616, 6200 MD Maastricht, The Netherlands
bResearch Institute Growth and Development (GROW), Department of Pathology,
University Maastricht, 6200 MD Maastricht, The Netherlands
Received 23 February 2006; received in revised form 24 May 2006; accepted 8 June 2006
Abstract
The first metabolite of alcohol, acetaldehyde, may trigger replication errors and mutations in DNA, which may predispose to developing
colorectal cancer (CRC). In a prospective study on colon and rectal cancer, we investigated the following hypotheses: alcohol consumption
is associated with an increased risk of mutations in the K-ras oncogene, and beer consumption is associated with an increased risk of G/
A mutations in this gene. Therefore, we studied the associations between consumption of alcohol and alcoholic beverages and the risk of
CRC without and with specific K-ras gene mutations. In 1986, 120,852 men and women, aged 55e69 years, completed a questionnaire on
risk factors for cancer. The caseecohort approach was used for data processing and analyses. After 7.3 years of follow-up, excluding the
first 2.3 years, complete data from 4,076 subcohort members, 428 colon and 150 rectal cancer patients, were available for data analyses.
Incidence rate ratios (RRs) and corresponding 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards models.
Compared to abstaining, a total alcohol consumption of 30.0 g/day and more was associated with the risk of colon and rectal cancer with
and without a K-ras mutation in both men and women. Independent from alcohol intake, liquor consumption when compared to nonliquor
consumption was associated with an increased risk of rectal cancer with a wild type K-ras in men (RR: 2.25, 95% CI: 1.0e5.0). Beer consumption
was not clearly associated with the risk of colon and rectal tumors harboring G/A mutations in the K-ras gene in men. This
association could not be assessed in women because of sparse beer consumption. In conclusion, alcohol does not seem to be involved in
predisposing to CRC through mutations in the K-ras gene, and specifically beer consumption is not associated with colon and rectal tumors
harboring a G/A mutation. 2006 Elsevier Inc. All rights reserved.
Keywords: Alcohol; Colorectal cancer; K-ras mutations; Cohort study; The Netherlands
1. 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 & 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 30e60% 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 &
* Corresponding author. Tel.: þ31-43-3882236; fax: þ31-43-3884128.
E-mail address: Brenda.Bongaerts@epid.unimaas.nl (B.W.C.
Bongaerts).
0741-8329/06/$ e see front matter 2006 Elsevier Inc. All rights reserved.
doi: 10.1016/j.alcohol.2006.06.003
Alcohol 38 (2006) 147e154

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