Alcohol consumption and molecular subtypes of colorectal cancer: pooled observational and Mendelian randomization analyses

Background Alcohol consumption is associated with colorectal cancer (CRC) risk, yet its association with distinct molecular subtypes remains unclear. Clarifying this could reveal insights into alcohol's carcinogenic mechanisms. Objective We examined 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 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 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 CRC, and across individual studies (P heterogeneity >0.05). MR analyses supported that higher genetically predicted alcohol consumption was associated with CRC risk (OR IVW-per 1SD =1.25; 95%CI: 1.01, 1.57), but similarly to the observational analysis, without evidence of heterogeneity across molecular subtypes. Conclusions Heavy alcohol consumption may initiate colorectal carcinogenesis through mechanisms that operate across all examined molecular pathways for CRC. Although the largest available data were used, power is lower for subtype heterogeneity analyses, and modest interaction effects cannot be excluded.