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Both inherited traits and tumor mutations affect response to treatment of leukemia

ited genes that can make the gene more or less effective, or might even have no effect at all.

In the present study, polymorphisms in two inherited genes, glutathione transferase (GSTM1) and thymidylate synthase (TYMS), predicted which children were at higher risk of bone marrow relapse. Children with at least one or two copies of the GSTM1 gene inherited from their parents are referred to as having "non-null" status. The GSTM1 gene also was associated with a higher risk of relapse. Approximately half the population inherits no normal copies of this gene and thus is at a lower risk of relapse. The GSTMI gene codes for an enzyme that breaks down certain drugs used to treat ALL, such as etoposide and cyclophosphamide, preventing them from killing cancer cells.

"The presence of the GSTM1 non-null polymorphism in a child means that the child has inherited the mechanism to more rapidly degrade some drugs," said Jose Claudio C. Rocha, M.D. Ph.D., a postdoctoral fellow on the project. "Having this information before therapy begins could mean that such patients might benefit by using therapy with more drugs that aren't broken down by GSTM1, or by increasing the dose levels of the drugs."

The 3/3 polymorphism of TYMS means that both maternal and paternal copies of the gene in the patient have a higher activity of TYMS, which acts like an accelerator in a car, driving leukemic cells ("blasts") to make new DNA rapidly, thus enabling the blasts to multiply. Cancer drugs targeting TYMS are used to put the brakes on this accelerator gene.

Previously identified risk factors for relapse included genetic mutations in the leukemia itself (BCR-ABL, MLL-AF4 or E2A-PBX1), a poor response to the early treatment and a very high number of white blood cells at diagnosis. The polymorphisms in GSTM1 alone or in combination with TYMS 3/3 independently increased the risk of relapse, regardless of these other risk factors for relapse, the researchers report.

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Contact: Bonnie Cameron
bonnie.cameron@stjude.org
901-495-4815
St. Jude Children's Research Hospital
2-Mar-2005


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