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Kendall, Heather E.

Microbiology and Molecular Genetics

2005

PhD

Survival rates of children treated for cancer have dramatically increased over the last 25 years as a result of the development of risk-directed multi-modality treatment protocols. As a result, there is a rapidly growing population of children and young adult cancer survivors in which the long-term genotoxic effects of chemotherapeutic intervention is unknown. The genotoxic effects of chemotherapy on children with hematological malignancies has been investigated by determining their mutant frequencies (Mfs) and mutational spectra at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) reporter gene locus, in non-malignant peripheral human T-cells. We have previously reported significantly elevated Mfs (30-1300 fold higher) in children following treatment for acute lymphocytic leukemia (ALL). In order to gain insight into the genotoxic effects and the etiology of the observed dramatic increase in Mfs following antineoplastic therapy, we investigated the incidence of microsatellite instability (MSI), reflective of a defect in DNA mismatch repair (MMR), HPRT mutation spectra, as well as the extent of clonal proliferation of HPRT mutant isolates, in children treated for ALL at diagnosis, during chemotherapy, and post-chemotherapy, compared to healthy age-matched controls.