Journal Article

DKFZ-2026-00982

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Alcohol consumption and molecular subtypes of colorectal cancer: pooled observational and Mendelian randomization analyses.

Chalitsios, C. V. ; Chan, W. C. ; Markozannes, G. ; Aglago, E. K. ; Berndt, S. I. ; Buchanan, D. D. ; Campbell, P. T. ; Cao, Y. ; Dimou, N. ; Drew, D. A. ; French, A. J. ; Gallinger, S. ; Georgeson, P. ; Giannakis, M. ; Gruber, S. B. ; Gunter, M. J. ; Harrison, T. A. ; Brenner, H.DKFZ* ; Hoffmeister, M.DKFZ* ; Urruchúa-Rodríguez, M.-J. ; Hsu, L. ; Huang, W.-Y. ; Hullar, M. A. ; Huyghe, J. R. ; Jenkins, M. A. ; Jayasekara, H. ; Moreno, V. ; Newton, C. C. ; Nowak, J. A. ; Obón-Santacana, M. ; Ogino, S. ; Pellatt, A. J. ; Peoples, A. ; Qu, C. ; Schmit, S. L. ; Steinfelder, R. S. ; Sun, W. ; Thomas, C. E. ; Toland, A. E. ; Trinh, Q. M. ; Ugai, T. ; Um, C. Y. ; Van Guelpen, B. ; Zaidi, S. H. ; Peters, U. ; Phipps, A. I. ; Tsilidis, K. K.

2026
Elsevier Amsterdam

Abstract: 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.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.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 average 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.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.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.

Keyword(s): CCFR ; GECCO ; alcohol ; colorectal cancer ; molecular epidemiology ; subtypes

Note: epub

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Contributing Institute(s):

1. C070 Klinische Epidemiologie der Krebsfrüherkennung (C070)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2026

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Database coverage:
; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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