{Reference Type}: Journal Article
{Title}: Folate intake and colorectal cancer risk according to genetic subtypes defined by targeted tumor sequencing.
{Author}: Aglago EK;Qu C;Harlid S;Phipps AI;Steinfelder RS;Ogino S;Thomas CE;Hsu L;Toland AE;Brenner H;Berndt SI;Buchanan DD;Campbell PT;Cao Y;Chan AT;Drew DA;Figueiredo JC;French AJ;Gallinger S;Georgeson P;Giannakis M;Goode EL;Gruber SB;Gunter MJ;Harrison TA;Hoffmeister M;Huang WY;Hullar MA;Huyghe JR;Jenkins MA;Lynch BM;Moreno V;Murphy N;Newton CC;Nowak JA;Obón-Santacana M;Sun W;Ugai T;Um CY;Zaidi SH;Tsilidis KK;van Guelpen B;Peters U;
{Journal}: Am J Clin Nutr
{Volume}: 120
{Issue}: 3
{Year}: 2024 Sep 16
{Factor}: 8.472
{DOI}: 10.1016/j.ajcnut.2024.07.012
{Abstract}: <B>BACKGROUND: </B>Folate is involved in multiple genetic, epigenetic, and metabolic processes, and inadequate folate intake has been associated with an increased risk of cancer.<BR><B>OBJECTIVE: </B>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.<BR><B>METHODS: </B>Participants within 2 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 nonsilent mutations in 105 genes and 6 signaling pathways (IGF2/PI3K, MMR, RTK/RAS, TGF-β, WNT, and TP53/ATM). Multinomial logistic regression models were analyzed comparing mutated/nonmutated CRC cases to controls to compute multivariable-adjusted odds ratios (ORs) with 95% confidence interval (CI). Heterogeneity of associations of mutated compared with nonmutated CRC cases was tested in case-only analyses using logistic regression. Analyses were performed separately in hypermutated and nonhypermutated tumors, because they exhibit different clinical behaviors.<BR><B>RESULTS: </B>We included 4339 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, and 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 toward 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 nonhypermutated tumors, or according to the signaling pathways.<BR><B>CONCLUSIONS: </B>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.