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Gene variant affecting metabolism cuts risk of childhood leukemias
By Roberta Friedman

Epidemiologists report a lower risk of childhood leukemias, if certain genetic variants of an enzyme involved in folate metabolism are present. In a study of samples collected from children in Great Britain, a polymorphism at two locations in the gene for methylenetetrahydrofolate reductase (MTHFR) has been associated with a lessened risk of two types of leukemias. The investigators in the United Kingdom and the U.S. speculate that the less risky alleles shift the metabolic balance to allow better copying of DNA, thus avoiding errors that lead to cancer.

Joseph Wiemels, assistant professor of epidemiology and biostatistics at the University of California Medical School, San Francisco, says, "there is a 2.8-fold protection imparted by [one] variant MTHFR allele for [a] particular leukemia subtype...the bottom line is that women should take plenty of folate before and during pregnancy."

Children with a C677T variant of the gene had relative protection from the form of leukemia with MLL translocations (with an odds ratio of 0.36). A lessened risk of hyperdiploid leukemia, a form of cancer where there are too many chromosomes, was found for children with an A1298C allele present in both copies of the gene (the odds ratio was 0.26). On the other hand, children with two copies of the C677T allele had an odds ratio of 0.49 for hyperdiploid leukemia. An odds ratio of one shows no association, says Wiemels, while a ratio less than one implies protection.

MTHFR serves as an important shunt for methyl groups, which must be added to various molecular building blocks important to DNA synthesis and the crafting of the body's proteins. Strand breaks in DNA due to deficient methylation are "the precursors for chromosome translocations and deletions," the investigators write in their report in Proceedings of the National Academy of Sciences.

The MTHFR polymorphisms of C677T and A1298C are common low-function variants, because they reduce, without entirely removing, the enzyme's activity. These low-function polymorphisms have been linked to an increased risk of vascular disease and neural tube defects, but—paradoxically enough—a lower risk of colon cancer. The scientists suggest that the lowered incidence of colon cancer could be due to the enzyme's unused pool of methyl groups, which is then available for DNA copying.

The study, which was carried out between 1992 and 1998 in the U.K., enrolled all new patients up to age 15 diagnosed with childhood leukemia. Samples were classified for the common molecular subgroups of pediatric leukemia. Control samples were collected from cord blood from healthy newborns. Two hundred controls and 250 children with leukemia were enrolled.

Altered MTHFR activity will derange folate, the nutrient linked to birth defects in the spine, cardiovascular disease, as well as some cancers. "Pregnancy is a time of extreme folate requirement," the researchers write. "Given the common in utero origin of childhood leukemia translocations and the high demands for folate, we predicted that MTHFR low-function alleles would confer protection." There is also evidence that these alleles protect against leukemia in adults, the investigators add.

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Wiemels, J.L. et al. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. Proc Natl Acad Sci USA 98, 4004-4009 (March 27, 2001).

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