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BACKGROUND: Red meat consumption is a risk factor for colorectal cancer (CRC) and has been linked to tumor alkylating DNA damage. rs16906252-T is a cis expression quantitative trait locus (eQTL) variant associated with silencing of MGMT, a central alkylating damage repair gene. We hypothesize that rs16906252-T carriers are predisposed to alkylating damage mutations.METHODS: We conducted mutational signature deconvolution of CRC whole-exome sequencing data from The Cancer Genome Atlas (TCGA, n = 540), the Nurses' Health Studies/ Health Professional Follow-up Study (NHS/HPFS, n = 900) as well as non-western samples from the Pan-Cancer Analysis of Whole Genomes (COCA-CN, n = 295); and examined the relationship of rs16906252-T with putative alkylation-dependent tumor mutations. Leveraging lifestyle data from NHS/HPFS, we also investigated the interaction between red meat consumption and rs16906252-T.RESULTS: Among CRC patients, rs16906252-T carriers exhibited higher tumor alkylating damage compared to non-carriers. In the general population, rs16906252-T is largely absent in individuals with East Asian ancestries, and we consistently find a negligible contribution of alkylating damage in CRC patients with East Asian ancestries. We show that the alkylating mutational signature's carcinogenicity is mainly mediated by KRAS G12D and G13D mutations. We also observe a synergistic effect of rs16906252-T with high pre-diagnosis red meat intake for tumor alkylating damage.CONCLUSIONS: MGMT rs16906252-T carriers are predisposed to CRC oncogenic alkylating damage which is potentiated by red meat intake.IMPACT: Our results support a causal relationship between red meat and CRC and may inform tailored dietary and screening guidelines for CRC prevention.