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    William E. Evans, PharmD

    Good pharmacogenomics requires counting chromosomes

    A team of St. Jude investigators has reported that the acquisition of additional chromosomes in cancer cells can create discord between host genome variability and inherited cancer cell phenotypes.

    The finding is important because genetic tests aimed at predicting the response of patients to anticancer drugs—a field called pharmocogenomics—usually look only at the normal DNA genotypes to diagnose inherited determinants of drug response; this process assumes two copies of each chromosomes are in all cells.

    Leukemic cells with duplicate copies of certain chromosomes will respond differently than would be predicted by looking only at the genetic makeup of germline (normal) cells, said Qing Cheng, PhD, a Pharmaceutical Sciences postdoctoral research associate. Cheng is the first author of a report on this work that appears in the August issue of Nature Genetics.

    The finding offers clinicians a more exacting way to predict whether a child with acute lymphoblastic leukemia will respond well or poorly to either methotrexate or mercaptopurine (MP), two of the major chemotherapy drugs used to treat this cancer. The quantitative genotyping method used to make these new findings can be used in other cancers that acquire additional chromosomes.

    Specifically, the study showed that leukemic cells can have an additional chromosome containing a wildtype (normal) copy of either the TPMT or GGH gene, which magnifies their effects. In leukemic cells that had an extra chromosome containing the TPMT gene, there was a significantly lower accumulation of the activated form of MP. In leukemic cells with an extra chromosome carrying a gene called GGH, a cellular pump that rids the cell of methotrexate was especially active, thereby reducing the amount of that anti-cancer drug in the leukemic cell.

    “In cancer cells with additional chromosomes, looking at the genetic makeup of only the normal cells isn’t sufficient to make an unequivocal diagnosis of a pharmacogenetic trait,” Cheng said. “It will make a difference whether the extra chromosome carries a normal or variant form of the gene of interest, and this could affect the way the cell handles the drug. Children might not get high enough levels of activated drug, or the drug might accumulate to toxic levels.”

    Pharmacogenomics is a powerful tool for designing effective treatments while minimizing toxicity, Cheng said. However, to make the most of this technique it is necessary to study the genotype and chromosomal makeup of the leukemic cells, and not rely solely on the genotype of normal tissues.

    Other authors of this report include Susana Raimondi, PhD, Pathology; Ching-Hon Pui, MD, Hematology-Oncology; and Wenjian Yang; Mary Relling, PharmD, chair; and hospital director William Evans, PharmD, senior author of the report, all of Pharmaceutical Sciences.

    The article by Cheng et al. received special attention in the “News and Views” section of the same issue of Nature Genetics.

    Last update: August 2005