Genetic variants may ease leukemia risk.

People with acute lymphocytic leukemia are more likely than healthy people to have the common version of a gene that plays a role in regulating folic acid metabolism in the body, a new study shows.

The gene encodes the enzyme methylene-tetrahydrofolate reductase (MTHFR), which acts on folic acid, a vitamin critical for DNA synthesis and repair. The common MTHFR gene produces a version of this enzyme that directs some of the folic acid toward other biological processes, reducing the amount available for proper DNA maintenance, the researchers find. Scientists have evidence that poor DNA repair triggers the growth of cancerous cells.

Folic acid deficiency may thus play a role in acute lymphocytic leukemia, a team of U.S. and British scientists report in the Oct. 26 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (PNAS). As many as two-thirds of people have the common form of the MTHFR gene.

Using blood DNA, the researchers compared the genetic makeup of 308 patients in England that have various leukemias with that of 491 healthy adults matched for sex, age, lifestyle, and geographic location. Most of the patients had acute myeloid leukemia and were no more likely to have the gene variation than healthy volunteers were.

However, the 71 patients with acute lymphocytic leukemia were significantly more likely to carry the common gene version than were 114 matched healthy people, says study coauthor Christine F. Skibola, a toxicologist at the University of California, Berkeley School of Public Health.

The healthy people were four times as likely to have a variation at a site on the gene called MTHFR-677 than were patients with lymphocytic leukemia, also called acute lymphoblastic leukemia. The healthy participants were also three times as likely to have a change at another site, MTHFR-1298, as these leukemia patients, Skibola says.

The study "is very provocative and may provide some insight into the development of [acute lymphocytic leukemia]," says Joseph R. Bertino, a pharmacologist at Memorial Sloan-Kettering Cancer Center in New York.

Earlier work showed that folic acid deficiency causes breaks in chromosomes, which contain DNA, and that folic acid supplements can prevent such breaks. Also, two previous studies linked the less common MTHFR-677 form with a reduced risk of colon cancer.

The new study reinforces the value of dietary folic acid, says Bruce N. Ames of the Department of Cell and Molecular Biology at Berkeley in the same issue of PNAS. "Chromosome breaks could contribute to the increased risk of cancer associated with [folic-acid] deficiency in humans," he says.

Bertino cautions, however, that the same variants of MTHFR that may help protect people against lymphocytic leukemia also seem to hike blood concentrations of homocysteine, a chemical linked to cardiovascular problems.