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BACKGROUND: Folate is involved in multiple genetic, epigenetic, and metabolic processes, and inadequate folate intake has been associated with an increased risk of cancer.OBJECTIVE: We examined whether folate intake is differentially associated with colorectal cancer (CRC) risk according to somatic mutations in genes linked to CRC using targeted sequencing.DESIGN: Participants within two large CRC consortia with available information on dietary folate, supplemental folic acid, and total folate intake were included. Colorectal tumor samples from cases were sequenced for the presence of non-silent mutations in 105 genes and 6 signaling pathways (IGF2/PI3K, MMR, RTK/RAS, TGF-β, WNT, TP53/ATM). Multinomial logistic regression models were run comparing mutated/non-mutated CRC cases to controls to compute multivariable-adjusted odds ratios (ORs) with 95% confidence intervals (CI). Heterogeneity of associations of mutated versus non-mutated CRC cases was tested in case-only analyses using logistic regression. Analyses were performed separately in hypermutated and non-hypermutated tumors, as they exhibit different clinical behaviors.RESULTS: We included 4,339 CRC cases (702 hypermutated tumors, 16.2%) and 11,767 controls. Total folate intake was inversely associated with CRC risk (OR=0.93, 95%CI=0.90-0.96). Among hypermutated tumors, 12 genes (AXIN2, B2M, BCOR, CHD1, DOCK3, FBLN2, MAP3K21, POLD1, RYR1, TET2, UTP20, ZNF521) showed nominal statistical significance (P<0.05) for heterogeneity by mutation status, but none remained significant after multiple testing correction. Among these genetic subtypes, the associations between folate variables and CRC were mostly inverse or towards the null, except for tumors mutated for DOCK3 (supplemental folic acid), CHD1 (total folate), and ZNF521 (dietary folate) that showed positive associations. We did not observe differential associations in analyses among non-hypermutated tumors, or according to the signaling pathways.CONCLUSIONS: Folate intake was not differentially associated with CRC risk according to mutations in the genes explored. The nominally significant differential mutation effects observed in a few genes warrants further investigation.