Over the last 20 years marked improvements in survival from childhood cancer have been achieved, at least in part by significant increases in the dose intensity of chemotherapy administered. While this has improved survival from the primary malignancy, increases in dose intensity have been associated with a marked increase in the frequency of therapy-related acute myeloid leukemia or myelodysplasia (t-MDS/AML), with frequencies as high as 22% in a Children's Cancer Group (CCG) treatment protocol for children with Ewing's sarcoma. The applicant hypothesizes that it is possible to identify genetic markers of alkylator damage to predict risk of t-MDS/AML in children receiving high dose-alkylating agent chemotherapy for sarcoma. Additionally, she hypothesizes that host genetic polymorphisms in drug metabolizing enzymes will influence genetic susceptibility to t-MDS/AML and could be used in the future to guide therapy. In this study she will investigate markers of genetic susceptibility and increased risk of t-MDS/AML in 321 children enrolled on CCG sarcoma treatment protocols. She will ask whether genetic susceptibility to alkylating agent damage can be measured prospectively (using analysis of glutathione-S-transferase genotype and glycophorin A mutation frequency). She will look for early signs of development of myeloid malignancy (clonal hematopoiesis), and for acquisition of later genetic events associated with myeloid malignancy (presence of ras gene mutations in peripheral blood leukocytes) in patients who have completed intensive chemotherapy. The identification of markers of genetic susceptibility to t-MDS/AML will allow future modification of therapy for individual patients. The identification of markers of early progression to t-MDS/AML during or after therapy will also allow modification of therapy and/or the development of treatment with chemopreventive agents such as retinoids.
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