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MTHFR and ALL risk: A challenge

The exact relationship between genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to childhood acute lymphoblastic leukemia (ALL) is not entirely established. A thorough elucidation of this topic is important, as it will improve the knowledge of the pathogenesis of ALL and possibly give new insights that may lead to the individualization of chemotherapy in ALL and contribute to leukemia prevention. MTHFR plays a central control role in folate metabolism and is an important factor in DNA methylation, synthesis and repair. One of the factors involved in the pathogenesis of leukemia is the alteration of the intra-cellular folate pool. This is most likely the result of pleiotropic genetic and environmental interactions. In this issue of Leukemia & Lymphoma, Reddy and Jamil [1] report that the MTHFR 677C4T and 1298A4C variants are associated with childhood ALL in an Indian population. These two polymorphisms are commonly found at varying frequencies in populations of different ethnic backgrounds. The allelic frequencies of the T allele at 677 or the C allele at 1298 range from 55% to *50% in different ethnic groups [2,3]. They are both associated with increased thermolability and significantly lower specific activity of the enzyme [4]. In particular, patients with the 677 variant have impaired remethylation of homocysteine to methionine and subsequent hyperhomocysteinemia and diminished genomic DNA methylation. Misincorporation of uracil into DNA leading to DNA strand breaks has also been associated with the same MTHFR variants [5]. Although additional MTHFR variants exist, most of the cancer risk epidemiology studies have been focused on the 677 variant. An increased risk associated with the 677 TT genotype for esophageal squamous-cell and gastric carcinoma and other cancers has been reported. However, a decreased risk associated with the TT genotype has been fairly consistent in studies in colorectal cancer, regardless of the folate intake of study subjects [6]. As discussed in the paper of Reddy and Jamil, similar discrepancies have been observed also for the risk of ALL, where the 677 variant was associated with either increased or decreased risk of developing the disease. In addition, other studies reported no association with ALL. Discrepancies may be related to the geographic origin of cases and controls, inadequate matching of controls, variable sample sizes and different effects of dietary folate intake across different studies. In Reddy and Jamil’s results, individuals with at least one variant allele (677 CTþTT or 1298 ACþCC) had an increased risk of developing ALL and the combined heterozygosity 677CT/1298AC showed the highest incidence of childhood ALL, suggesting a synergistic effect between these two variants. Moreover, male children were more susceptible to ALL compared to females due to the greater prevalence of MTHFR variants among males. However, these gender differences on the effect of MTHFR polymorphisms on childhood ALL must be critically reviewed. In particular, the folate intake can be a confounding factor and the gender difference in Reddy and Jamil’s study could also be due to different intake between males and females.