TY - JOUR
T1 - Folate intake and colorectal cancer risk according to genetic subtypes defined by targeted tumor sequencing
AU - Aglago, Elom K.
AU - Qu, Conghui
AU - Harlid, Sophia
AU - Phipps, Amanda I.
AU - Steinfelder, Robert S.
AU - Ogino, Shuji
AU - Thomas, Claire E.
AU - Hsu, Li
AU - Toland, Amanda E.
AU - Brenner, Hermann
AU - Berndt, Sonja I.
AU - Buchanan, Daniel D.
AU - Campbell, Peter T.
AU - Cao, Yin
AU - Chan, Andrew T.
AU - Drew, David A.
AU - Figueiredo, Jane C.
AU - French, Amy J.
AU - Gallinger, Steven
AU - Georgeson, Peter
AU - Giannakis, Marios
AU - Goode, Ellen L.
AU - Gruber, Stephen B.
AU - Gunter, Marc J.
AU - Harrison, Tabitha A.
AU - Hoffmeister, Michael
AU - Huang, Wen Yi
AU - Hullar, Meredith AJ
AU - Huyghe, Jeroen R.
AU - Jenkins, Mark A.
AU - Lynch, Brigid M.
AU - Moreno, Victor
AU - Murphy, Neil
AU - Newton, Christina C.
AU - Nowak, Jonathan A.
AU - Obón-Santacana, Mireia
AU - Sun, Wei
AU - Ugai, Tomotaka
AU - Um, Caroline Y.
AU - Zaidi, Syed H.
AU - Tsilidis, Konstantinos K.
AU - van Guelpen, Bethany
AU - Peters, Ulrike
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/9
Y1 - 2024/9
N2 - 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 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. Results: 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. 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.
AB - 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 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. Results: 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. 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.
KW - colorectal cancer
KW - folate
KW - folic acid
KW - molecular subtypes
KW - somatic mutations
KW - tumor
UR - http://www.scopus.com/inward/record.url?scp=85200746168&partnerID=8YFLogxK
U2 - 10.1016/j.ajcnut.2024.07.012
DO - 10.1016/j.ajcnut.2024.07.012
M3 - Article
C2 - 39025327
AN - SCOPUS:85200746168
SN - 0002-9165
VL - 120
SP - 664
EP - 673
JO - American Journal of Clinical Nutrition
JF - American Journal of Clinical Nutrition
IS - 3
ER -