Inherited traits and tumor mutations affect response to treatment of leukemia

The outcome of chemotherapy treatment for acute lymphoblastic leukemia (ALL) depends not only on the acquired genetic make-up of the leukemic cells, but on genes that children inherit from their parents. This study, from investigators at St. Jude Children's Research Hospital, is published in the online edition of Blood.

The study provides strong evidence that it might be possible to design ALL treatment based in part on an individual patient's inherited genetic makeup. ALL is the most common tumor in children and affects the cells of the bone marrow. Currently, gene-based individualization of treatments is based only on the genetic mutations of leukemic cells. Chemotherapy must be more aggressive and may have more side effects if leukemic cells have genetics indicating a higher risk of relapse than if the leukemia cells indicate a lower risk of relapse. So-called germline (inherited) genetic characteristics are generally not used to identify children at high risk for relapse. But that could change because of the findings of this study, the researchers suggest.

The St. Jude team demonstrated that certain traits inherited from parents could reduce the effectiveness of some cancer chemotherapy. The findings therefore have the potential to improve treatment outcome by providing additional genetic clues that enable clinicians to identify patients at high or low risk of relapsing, according to Mary Relling, Pharm.D., chair of St. Jude Pharmaceutical Sciences and senior author of the Blood report.

"Therapy for ALL usually lasts two to three years," Relling said. "So over such a long period, even small changes that affect the potency of cancer drugs could have a major influence on the outcome of treatment."

The goal of the St. Jude study was to determine whether the success or failure of chemotherapy for ALL was linked to any of 16 common genetic polymorphisms in genes that interact with the ALL chemotherapy. Polymorphisms are slight variations in inherited 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.

The researchers made their discovery in a study of genes in both normal and leukemic cells from 246 children with ALL. A total of 116 of patients constituted the lower-risk group and 130 were in the higher-risk group. Patients in the higher-risk group who had both the GSTM1 non-null polymorphism and the TYMS 3/3 polymorphism were 14 times more likely to relapse than patients who inherited other gene polymorphisms at GSTM1 and TYMS. None of the originally targeted 16 polymorphisms, including GSTM1 and TYMS were linked to risk of failure in the lower-risk group.

The researchers concluded that GSTM1 and TYMS, are likely linked to resistance to specific cancer drugs, and that treatment of ALL might be improved in higher-risk patients if therapies were modified to take these inherited risk factors into account.

Other authors of this paper are Cheng Cheng, Wei Liu, Shinji Kishi, John T. Sandlund, Jeffrey Rubnitz, Raul Ribeiro, Dario Campana, Ching-Hon Pui and William E. Evans (St. Jude) and Soma Das and Edwin H. Cook (University of Chicago).