Abstract
BackgroundOne-carbon metabolism appears to play an important role in DNA methylation reaction. Evidence suggests that a low intake of B vitamins or high alcohol consumption increases colorectal cancer risk. How one-carbon nutrients affect the CpG island methylator phenotype (CIMP) or BRAF mutation status in colon cancer remains uncertain.MethodsUtilizing incident colon cancers in a large prospective cohort of women (the Nurses' Health Study), we determined BRAF status (N = 386) and CIMP status (N = 375) by 8 CIMP-specific markers [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and 8 other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT-1, MINT-31, p14, and WRN). We examined the relationship between intake of one-carbon nutrients and alcohol and colon cancer risk, by BRAF mutation or CIMP status.ResultsHigher folate intake was associated with a trend towards low risk of CIMP-low/0 tumors [total folate intake ≥400 µg/day vs. <200 µg/day; the multivariate relative risk = 0.73; 95% CI = 0.53–1.02], whereas total folate intake had no influence on CIMP-high tumor risks (Pheterogeneity = 0.73). Neither vitamin B6, methionine or alcohol intake appeared to differentially influence risks for CIMP-high and CIMP-low/0 tumors. Using the 16-marker CIMP panel did not substantially alter our results. B vitamins, methionine or alcohol intake did not affect colon cancer risk differentially by BRAF status.ConclusionsThis molecular pathological epidemiology study suggests that low level intake of folate may be associated with an increased risk of CIMP-low/0 colon tumors, but not that of CIMP-high tumors. However, the difference between CIMP-high and CIMP-low/0 cancer risks was not statistically significant, and additional studies are necessary to confirm these observations.
Highlights
DNA methylation is an important epigenetic mechanism in gene silencing and imprinting [1,2,3]
DNMT3B has emerged as one of causes of CpG island methylation in tumor [12,13,14]; the association between DNMT3B and CpG island methylator phenotype (CIMP) in colorectal cancer is at most modest [13] and tumor CpG island methylation appears to be influenced by additional factors
We have recently shown that adequate folate intake and low consumption of alcohol are protective against LINE-1 hypomethylated colon cancer, but not against LINE-1 hypermethylated colon cancer [20]
Summary
DNA methylation is an important epigenetic mechanism in gene silencing and imprinting [1,2,3]. Aberrant epigenetic silencing of tumor suppressors by CpG island hypermethylation is commonly observed in human malignancies. Despite a strong association between CIMP and BRAF mutation in colorectal cancer [5,6,7,8], the hypothesis that BRAF mutation causes aberrant CpG island methylation [10] has been highly controversial [11]. DNMT3B has emerged as one of causes of CpG island methylation in tumor [12,13,14]; the association between DNMT3B and CIMP in colorectal cancer is at most modest [13] and tumor CpG island methylation appears to be influenced by additional factors. How one-carbon nutrients affect the CpG island methylator phenotype (CIMP) or BRAF mutation status in colon cancer remains uncertain
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