Clinical Research
Copyright ©2008 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Jun 21, 2008; 14(23): 3662-3671
Published online Jun 21, 2008. doi: 10.3748/wjg.14.3662
Methylenetetrahydrofolate reductase C677T genotype affects promoter methylation of tumor-specific genes in sporadic colorectal cancer through an interaction with folate/vitamin B12 status
Pooneh Mokarram, Fakhraddin Naghibalhossaini, Mehdi Saberi Firoozi, Seyed Vahid Hosseini, Ahmad Izadpanah, Heshmetalah Salahi, Seyed Ali Malek-Hosseini, Abdoulrasool Talei, Mehra Mojallal
Pooneh Mokarram, Fakhraddin Naghibalhossaini, Department of Biochemistry, Shiraz University of Medical Sciences, School of Medicine, Shiraz 71345, Iran
Mehdi Saberi Firoozi, Department of Internal Medicine and Gastroenterohepatology Research Centre, Shiraz University of Medical Sciences, Shiraz 71345, Iran
Seyed Vahid Hosseini, Ahmad Izadpanah, Department of Surgery (colorectal ward) and Gastroenterohepatology Research Centre, Shiraz University of Medical Sciences, Shiraz 71345, Iran
Heshmetalah Salahi, Seyed Ali Malek-Hosseini, Department of Surgery and Organ Transplantation Research Centre, Namazee Hospital, Shiraz University of Medical Sciences, Shiraz 71345, Iran
Abdoulrasool Talei, Department of Surgery and Institute of Cancer Research, Shiraz University of Medical Sciences, Shiraz 71345, Iran
Mehra Mojallal, Pathology Laboratory, Dena Hospital, Shiraz 71345, Iran
Author contributions: Naghibalhossaini F designed research and wrote the paper; Hosseini SV, Saberi Firoozi M, Izadpanah A, Salahi H, Malek-Hosseini SA, Talei A, and Mojallal M provided specimens, reagents and analytical tools; Mokarram P performed research.
Correspondence to: Fakhraddin Naghibalhossaini, Department of Biochemistry, Shiraz University of Medical Sciences, School of Medicine, Zand Street, Shiraz 71345, Iran. fakhraddin.naghibalhossaini@elf.mcgill.ca
Telephone: +98-711-2303029
Fax: +98-711-2303029
Received: February 18, 2008
Revised: April 15, 2008
Accepted: April 22, 2008
Published online: June 21, 2008
Abstract

AIM: To evaluate joint effects of Methylentetrahydrofolate reductase (MTHFR) C677T genotypes, and serum folate/vitamin B12 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 B12 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 B12 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 B12 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).

CONCLUSION: We conclude that high concentrations of serum folate/vitamin B12 levels are associated with the risk of promoter methylation in tumor-specific genes, and this relationship is modified by MTHFR C677T genotypes.

Keywords: Methylentetrahydrofolate reductase; Folate; Vitamin B12; Methylation; Colorectal cancer