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

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Abstract

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.

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Acknowledgments

The authors’ thanks to Dr. Shakaib Siddiqui for providing clinical information and Azadali Moorji for technical assistance.

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Authors and Affiliations

  1. Department of Human Cancer Genomic Research Centre, King Fahad National Center for Children’s Cancer and Research, Riyadh, Saudi Arabia

    Abdul K. Siraj, Muna Ibrahim, Maha Al-Rasheed, Rong Bu, Prashant Bavi, Zeenath Jehan, Jehad Abubaker, Shahab Uddin & Khawla Al-Kuraya

  2. Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

    Walid Murad & Fouad Al-Dayel

  3. King Faisal Cancer Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

    Adnan Ezzat

  4. Pediatric Hematology–Oncology, King Fahad National Center for Children’s Cancer and Research, Riyadh, Saudi Arabia

    Hassan El-Solh

  5. Department of Human Cancer Genomic Research, King Fahad National Center for Children’s Cancer and Research, King Faisal Specialist Hospital and Research Center, MBC#98-16, P.O. Box 3354, Riyadh, 11211, Saudi Arabia

    Khawla Al-Kuraya

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  1. Abdul K. Siraj
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Correspondence to Khawla Al-Kuraya.

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Siraj, A.K., Ibrahim, M., Al-Rasheed, M. et al. 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 86, 887–895 (2007). https://doi.org/10.1007/s00277-007-0350-2

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