One-carbon metabolism and CpG island methylator phenotype status in incident colorectal cancer: a nested case-referent study.
OBJECTIVE
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).


METHODS
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.


RESULTS
A reduced risk of CIMP-low/CIMP-high CRC (> or =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)].


CONCLUSIONS
Though limited by low power, these findings suggest the possibility of different roles for one-carbon metabolism in different pathways of colorectal tumorigenesis.
Van Guelpen
Bethany
B
Department of Medical Biosciences, Pathology, Umeå University, Building 6M, 2nd Floor, 90185 Umeå, Sweden. bethany.van.guelpen@medbio.umu.se
Dahlin
Anna M
AM
Hultdin
Johan
J
Eklöf
Vincy
V
Johansson
Ingegerd
I
Henriksson
Maria L
ML
Cullman
Inger
I
Hallmans
Göran
G
Palmqvist
Richard
R
D000368:Aged; D002244:Carbon / Q000378:metabolism*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D005492:Folic Acid / Q000097:blood; D020022:Genetic Predisposition to Disease; D006710:Homocysteine / Q000097:blood; D006801:Humans; D015994:Incidence; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013548:Sweden / Q000453:epidemiology; D014805:Vitamin B 12 / Q000097:blood
D006710:Homocysteine; D002244:Carbon; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D014805:Vitamin B 12