Alcohol consumption and molecular subtypes of colorectal cancer: pooled observational and Mendelian randomization analyses.
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Chalitsios Christos V, Chan Wing Ching, Markozannes Georgios, Aglago Elom K, Berndt Sonja I, Buchanan Daniel D, Campbell Peter T, Cao Yin, Dimou Niki, Drew David A, French Amy J, Gallinger Steven, Georgeson Peter, Giannakis Marios, Gruber Stephen B, Gunter Marc J, Harrison Tabitha A, Brenner Hermann, Hoffmeister Michael, Urruchúa-Rodríguez Mary-Jose, Hsu Li, Huang Wen-Yi, Hullar Meredith Aj, Huyghe Jeroen R, Jenkins Mark A, Jayasekara Harindra, Moreno Victor, Newton Christina C, Nowak Jonathan A, Obón-Santacana Mireia, Ogino Shuji, Pellatt Andrew J, Peoples Anita, Qu Conghui, Schmit Stephanie L, Steinfelder Robert S, Sun Wei, Thomas Claire E, Toland Amanda E, Trinh Quang M, Ugai Tomotaka, Um Caroline Y, Van Guelpen Bethany, Zaidi Syed H, Peters Ulrike, Phipps Amanda I, Tsilidis Konstantinos K
Аннотация
OBJECTIVES: We examined the association between alcohol consumption and the risk of CRC subtypes defined by individual tumor markers (and marker combinations), namely microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP) status, BRAF, and KRAS mutations.
METHODS: Pooled observational (ncases = 11,826, ncontrols = 10,888; nstudies = 10) and genome-wide association data (ncases = 8178, ncontrols = 10,472; nstudies = 10) were used. Multivariable logistic regression models and Mendelian randomization (MR) analyses were conducted to assess the association between alcohol consumption, modeled in MR as genetically predicted mean drinks per week per 1 SD increase (≈2.9 drinks/wk), and risk of CRC subtypes defined by individual tumor 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/d of alcohol was associated with a 10% higher CRC risk [odds ratio (OR) = 1.10; 95% confidence interval (CI): 1.07, 1.13], but this association was primarily driven by heavy alcohol consumption (>28 g/d). Including nondrinkers revealed a J-shaped association (P-nonlinearity = 0.002). The associations with higher alcohol consumption were stronger in males compared with females. No significant heterogeneity was observed across MSI, CIMP, BRAF, or KRAS-defined subtypes. All associations were similar across smoking status, folate intake, tumor 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 (ORIVW-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.