Methylenetetrahydrofolate reductase C677T genotype affects promoter methylation of tumor-specific genes in sporadic colorectal cancer through an interaction with folate/vitamin B12 status.
OBJECTIVE
To evaluate joint effects of Methylentetra-hydrofolate reductase (MTHFR) C677T genotypes, and serum folate/vitamin B(12) concentrations on promoter methylation of tumor-associated genes among Iranian colorectal cancer patients.


METHODS
We examined the associations between MTHFR C677T genotype, and promoter methylation of P16, hMLH1, and hMSH2 tumor-related genes among 151 sporadic colorectal cancer patients. The promoter methylation of tumor-related genes was determined by methylation-specific PCR. Eighty six patients from whom fresh tumor samples were obtained and 81 controls were also examined for serum folate and vitamin B(12) concentrations by a commercial radioimmunoassay kit.


RESULTS
We found 29.1% of cases had tumors with at least one methylated gene promoter. In case-case comparison, we did not find a significant association between methylation in tumors and any single genotype. However, in comparison to controls with the CC genotype, an increased risk of tumor methylation was associated with the CT genotype (OR = 2.5; 95% CI, 1.1-5.6). In case-case comparisons, folate/vitamin B(12) levels were positively associated with tumor methylation. Adjusted odds ratios for tumor methylation in cases with high (above median) versus low (below median) serum folate/vitamin B(12) levels were 4.9 (95% CI, 1.4-17.7), and 3.9 (95% CI, 1.1-13.9), respectively. The frequency of methylated tumors was significantly higher in high methyl donor than low methyl donor group, especially in those with MTHFR CT (P = 0.01), and CT/TT (P = 0.002) genotypes, but not in those with the CC genotype (P = 1.0).


CONCLUSIONS
We conclude that high concentrations of serum folate/vitamin B(12) levels are associated with the risk of promoter methylation in tumor-specific genes, and this relationship is modified by MTHFR C677T genotypes.
Mokarram
Pooneh
P
Department of Biochemistry, Shiraz University of Medical Sciences, School of Medicine, Shiraz 71345, Iran.
Naghibalhossaini
Fakhraddin
F
Saberi Firoozi
Mehdi
M
Hosseini
Seyed Vahid
SV
Izadpanah
Ahmad
A
Salahi
Heshmetalah
H
Malek-Hosseini
Seyed Ali
SA
Talei
Abdoulrasool
A
Mojallal
Mehra
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D005492:Folic Acid / Q000097:blood*; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D007492:Iran; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D018570:Risk Assessment; D014805:Vitamin B 12 / Q000097:blood*
D048868:Adaptor Proteins, Signal Transducing; D019941:Cyclin-Dependent Kinase Inhibitor p16; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D014805:Vitamin B 12