Background
Alcohol consumption is associated with higher colorectal cancer (CRC) risk, yet its association with distinct molecular subtypes of the disease remains unclear. Clarifying this could reveal insights into alcohol's carcinogenic mechanisms.

Objective
We aimed to examine the association between alcohol consumption and the risk of CRC subtypes defined by individual tumour markers (and marker combinations), namely microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP) status, BRAF and KRAS mutations. 

Methods
Pooled observational (n_cases=11,826, n_controls=10,888; n_studies=10) and genome-wide association data (n_cases=8,178, n_controls=10,472; n_studies=10) were utilised. Multivariable logistic regression models and Mendelian randomisation (MR) analyses were conducted to assess the association between alcohol consumption, modelled in MR as genetically predicted average drinks per week per one standard deviation increase (≈2.9 drinks/week), and the risk of CRC subtypes defined by individual tumour markers (and marker combinations). Case-only analyses tested for differences between molecular subtypes. Bonferroni correction was applied to account for multiple tests.

Results
Among drinkers, each additional 14 g/day of alcohol was associated with a 10% higher CRC risk (OR=1.10; 95%CI: 1.07, 1.13), but this association was primarily driven by heavy alcohol consumption (>28g/d). Including non-drinkers revealed a J-shaped association (P_{non-linearity}=0.002). The associations with higher alcohol consumption were stronger in males compared to females. No significant heterogeneity was observed across MSI, CIMP, BRAF, or KRAS-defined subtypes. All associations were similar across smoking status, folate intake, tumour anatomical site, study design, early/late onset, and across individual studies (P_{heterogeneity}>0.05). MR analyses supported that higher genetically predicted alcohol consumption was associated with CRC risk (OR_{per 1SD}=1.28; 95%CI: 1.05, 1.56), but similarly to the observational analysis, without evidence of heterogeneity across molecular subtypes.

Conclusions/Implications for practice or policy
Our study suggests that heavy alcohol consumption initiates colorectal carcinogenesis through mechanisms that operate across all major molecular pathways for CRC. The results support existing public health guidelines advocating for reduced alcohol consumption and underscore the relevance of lifestyle-based prevention strategies across the four 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.