Individuals with high alcohol consumption are at increased risk of colorectal cancer (CRC), reports a study, which shows that alcohol intake may trigger colorectal carcinogenesis through mechanisms operating across major molecular pathways for CRC.
“These findings seem to suggest that alcohol may act through mechanisms that transcend specific tumour molecular profiles,” said the investigators, who performed pooled observational and Mendelian randomization (MR) analyses.
Among drinkers, each additional 14-g/day of alcohol contributed to a 10-percent higher likelihood of developing CRC (odds ratio [OR], 1.10, 95 percent confidence interval [CI], 1.07‒1.13), although this association was mostly driven by heavy alcohol consumption (>28 g/day). The inclusion of nondrinkers showed a J-shaped association (pnonlinearity=0.002). [Am J Clin Nutr 2026;123:101308]
The associations between CRC risk and heavy alcohol consumption were more pronounced in males than in females. Moreover, significant heterogeneity was not observed across microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP) status, BRAF, and KRAS mutations.
Similar associations were noted across smoking status, folate intake, tumour anatomical site, study design, early/late-onset CRC, and across individual studies (pheterogeneity>0.05).
In MR analyses, higher genetically predicted alcohol consumption showed a significant association with CRC risk (OR, 1.25, 95 percent CI, 1.01‒1.57). Similar to the observational analysis, no evidence of heterogeneity across molecular subtypes was seen.
“Our results support existing public health guidelines advocating for reduced alcohol consumption and underscore the relevance of lifestyle-based prevention strategies across … major molecular pathways defined by BRAF, KRAS, CIMP, and MSI status in colorectal carcinogenesis, although further stratification by alcohol-related molecular features may reveal subtype-specific differences,” the investigators said.
Mechanisms
The exact biological mechanisms connecting alcohol intake to CRC development is still unclear, but previous studies have proposed several possible pathways.
One hypothesis “involves the metabolic conversion of ethanol to acetaldehyde and … generation of reactive oxygen species, both of which can damage critical cellular components, including DNA, proteins, and lipids, leading to cellular dysfunction and increased oncogenic potential,” said the investigators. [Proc Nutr Soc 2006;65:278-290; Am J Physiol Gastrointest Liver Physiol 2005;289:G367-G375]
One potential mechanism suggests mucosal adhesion disruption in the colon with acetaldehyde, which promotes tyrosine phosphorylation, particularly in the presence of specific gut microbiota that allow its accumulation within the colonic lumen. [Exp Res 2000;24:570-575]
“This disruption compromises the integrity of adhesive proteins within the epithelium, thereby weakening intercellular junctions and enhancing cellular proliferation and migration processes central to tumour initiation and metastasis,” the investigators said. [Exp Res 2004;28:797-804]
Heavy alcohol consumption has also been linked to altered folate metabolism, a micronutrient necessary for DNA synthesis, repair, and methylation. [Am J Clin Nutr 2012;95:405-412; Mol Nutr Food Res 2013;57:596-606]
“Impaired folate status may therefore contribute to genomic instability and colorectal carcinogenesis,” the investigators said. “Moreover, alcohol-induced alterations in the gut microbiome—referred to as dysbiosis—may further promote inflammatory and carcinogenic processes within the colon.” [Gut 2017;66:633-643]
The current study used pooled observational (n=10 studies) and genome-wide association data (n=10 studies). The association between alcohol consumption and risk of CRC subtypes defined by individual tumour markers was explored via multivariable logistic regression models and MR analyses. Case-only analyses tested for differences between molecular subtypes.