One-carbon metabolism and CpG island methylator phenotype status in incident colorectal cancer: a nested case–referent study
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We related prediagnostic plasma folate, vitamin B12, and total homocysteine concentrations, and the MTHFR 677C>T and 1298A>C polymorphisms, to the risk of colorectal cancer with and without the CpG island methylator phenotype (CIMP).
This was a nested case–referent study of 190 cases and double, matched referents from the large, population-based Northern Sweden Health and Disease Study. Using archival tumor tissue, promoter methylation in an eight-gene panel was analyzed by MethyLight.
A reduced risk of CIMP-low/CIMP-high CRC (≥1 gene methylated) was observed in subjects with very low plasma folate concentrations [multivariate odds ratio 2.96 (95% CI 1.24–7.08) for quintiles two to five versus one (lowest)]. With the exception of a reduced risk in MTHFR 677 TT-homozygotes, none of the other one-carbon variables were associated with the risk of CIMP-low/CIMP-high CRC. For CIMP-negative CRC, only the MTHFR polymorphisms were statistically significantly related to risk, inversely for 677C>T and positively for 1298A>C, but a tendency toward a reduced risk was observed in subjects with an adequate methyl availability, combining the plasma variables [multivariate odds ratio 0.61 (95% CI 0.32–1.15)].
Though limited by low power, these findings suggest the possibility of different roles for one-carbon metabolism in different pathways of colorectal tumorigenesis.
KeywordsDNA methylation Folate Vitamin B12 Homocysteine MTHFR Colorectal cancer
We thank all participants in the VIP, MONICA, and MSP cohorts of the Northern Sweden Health and Disease Study, as well as Åsa Ågren of the Northern Sweden Medical Biobank, Umeå University. Thanks also to Kerstin Näslund and Le Thu Trinh of the Department of Medical Biosciences, Pathology, Umeå University and formerly of the Department of Medical Biosciences, Clinical Chemistry, Umeå University, respectively, for excellent technical assistance. The study was financially supported by grants from the Swedish Cancer Society, the Cancer Research Foundation in Northern Sweden, The Swedish Council for Working Life and Social Research, the Faculty of Medicine at Umeå University, Umeå, Sweden, a Cutting-Edge Research Grant from the County Council of Västerbotten, and the J. C. Kempe Memorial Fund.
Conflict of interest statement
The authors declare that they have no conflict of interests.
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