Genetic polymorphisms of methylenetetrahydrofolate reductase and promoter methylation of MGMT and FHIT genes in diffuse large B cell lymphoma risk in Middle East

Ann Hematol. 2007 Dec;86(12):887-95. doi: 10.1007/s00277-007-0350-2. Epub 2007 Aug 22.


Diffuse large B cell lymphoma (DLBCL) is one of the most common non-Hodgkin's lymphoma types. Methylenetetrahydrofolate reductase (MTHFR) balances the pool of folate coenzymes in one carbon metabolism of deoxyribonucleic acid (DNA) synthesis and methylation; both are implicated in carcinogenesis of many types of cancer including lymphoma. Two common variants in the MTHFR gene (C677T and A1298C) have been associated with reduced enzyme activity, thereby making MTHFR polymorphisms a potential candidate as a cancer-predisposing factor. The O6 methylguanine DNA methyltransferase (MGMT) and fragile histidine triad (FHIT) genes are transcriptionally silenced by promoter hypermethylation in DLBCL. These genetic differences are highly race specific and have never been screened in the Saudi DLBCL patients. We conducted a hospital-based case-control study including 160 DLBCL cases and 511 Saudi control samples analyzing the MTHFR C677T and A1298C functional polymorphisms by the restriction fragment length polymorphism method and their association with MGMT and FHIT genes promoter hypermethylation. Our data demonstrated that Saudi individuals carrying MTHFR genotype 1298CC (p < 0.001) and the 1298C allele (p = 0.012) had 4.23 and 1.73-fold higher risk of developing DLBCL, respectively. Additionally, combined genotype CCCC (MTHFR 677CC + MTHFR 1298CC) was associated with 3.489-fold, and CTCC (MTHFR 677 CT + 1298CC) was related to 9.515-fold higher risk, compared with full MTHFR enzyme activity. No significant association between MTHFR variant genotypes and methylation of MGMT and FHIT genes were observed. Our findings suggested that polymorphisms of MTHFR enzyme genes might be associated with the individual susceptibility to develop DLBCL. Additionally, the results indicated that MTHFR variants were not related to MGMT or FHIT hypermethylation in DLBCL.

MeSH terms

  • Acid Anhydride Hydrolases / genetics*
  • Adult
  • Base Sequence
  • DNA Methylation*
  • DNA Modification Methylases / genetics*
  • DNA Repair Enzymes / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / epidemiology
  • Lymphoma, Large B-Cell, Diffuse / genetics*
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Methylenetetrahydrofolate Reductase (NADPH2) / physiology
  • Middle Aged
  • Molecular Sequence Data
  • Mutation, Missense*
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / physiology
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic / genetics
  • Saudi Arabia / epidemiology
  • Tumor Suppressor Proteins / genetics*


  • Neoplasm Proteins
  • Tumor Suppressor Proteins
  • fragile histidine triad protein
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • DNA Modification Methylases
  • MGMT protein, human
  • Acid Anhydride Hydrolases
  • DNA Repair Enzymes