The objective of this work is to develop new avenues to identify undergoing anticancer therapy who are at increased risk of leukemia as a treatment complication and to facilitate detection of the leukemic clone earlier in the course of the disease. For children with metastatic neuroblastoma receiving N6 therapy, the incidence of leukemia is 7%. About 40% of cases are related to alkylating agent therapy and have chromosome 5 and/or 7 loss; about 40% have translocation of the MLL gene at chromosome band 11q23, which occurs in leukemias related to DNA topoisomerase II inhibitors. Because of its efficacy against neuroblastoma, N6 therapy will be incorporated into the high-risk neuroblastoma trial for the Children's Cancer Group. Etoposide, doxorubicin and cyclophosphamide used in N6 therapy are metabolized by cytochrome P-450 (CYP) 3A; all are associated with leukemia as a treatment complication. The metabolites have genotoxic properties that may be relevant to leukemogenesis. The promoter of the CYP3A4 gene is polymorphic. Prior studies showed that the CYP3A4 wild-type genotype increased and CYP3A4 variant genotypes decrease the risk of treatment-related leukemia with MLL gene translocations. Prior studies also showed that the MLL gene translocation can be present early in the course therapy at how cumulative doses of DNA topoisomerase II inhibitors. MLL presents an extreme example of a translocation involving many partner genes; Southern blot analysis and cDNA panhandle PCR are two methods that can track the translocations in preleukemic samples regardless of the partner gene. They hypothesize that CYP3A4 genotype and MLL gene translocations are relevant biomarkers for treatment-related leukemia. The plans of the cooperative group to use N6 therapy not only mandate systematic investigation of who is most at risk, but also provide a unique clinical opportunity to examine CYP3A4 genotype and MLL gene translocations as a relevant biomarkders in the context of the therapeutic trial. The purpose of aim 1 is to validate the association of CYP3A4 genotype with treatment-related leukemia. The purpose of aims 2 and 3 is to determine and compare the utility of MLL gene translocations, detected by Southern blot analysis and cDNA panhandle PCR, as leukemia-specific markers that predict development of disease. The purpose of aim 4 is to explore the baseline frequency of MLL gene translocations in untreated pediatric patients diagnosed with neuroblastoma and to determine how chemotherapy affects this frequency during the course of treatment. Risk factors for treatment-related leukemia are poorly understood. Predictive biomarker assays will enable rational modifications of primary cancer therapies and provide new opportunities for early intervention.
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