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

• Published in: Cancer causes & control 2010-04, Vol.21 (4), p.557-566
• Main Authors: Van Guelpen, Bethany, Dahlin, Anna M, Hultdin, Johan, Eklöf, Vincy, Johansson, Ingegerd, Henriksson, Maria L, Cullman, Inger, Hallmans, Göran, Palmqvist, Richard
• Format: Article
• Language: English
• Subjects: Aged; Biomedical and Life Sciences; Biomedicine; Blood plasma; Cancer; Cancer Research; Carbon; Carbon - metabolism; Case-Control Studies; Colorectal cancer; Colorectal Neoplasms - epidemiology; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; CpG Islands - genetics; DNA Methylation; Epidemiology; Epigenetics; Female; Folic Acid - blood; Genes; Genetic mutation; Genetic Predisposition to Disease; Genotype & phenotype; Hematology; Homocysteine; Homocysteine - blood; Humans; Incidence; Male; Metabolism; Methylation; Methylenetetrahydrofolate Reductase (NADPH2) - genetics; Middle Aged; Multivariate Analysis; Mutation; Nutrition research; Odds Ratio; Oncology; Original Paper; Phenotype; Phenotypes; Plasma; Polymorphism, Single Nucleotide; Public Health; Referents; Risk Factors; Sweden - epidemiology; Tissue samples; Tumorigenesis; Tumors; Vitamin B; Vitamin B 12 - blood; Vitamin B12
• ISSN: 0957-5243; 1573-7225; 1573-7225
• DOI: 10.1007/s10552-009-9484-y

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 (≥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)]. Conclusion Though limited by low power, these findings suggest the possibility of different roles for one-carbon metabolism in different pathways of colorectal tumorigenesis.