Drug Metabolism, DNA Repair & Second Cancers

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DESCRIPTION (provided by applicant): Candidate: Dr. Friedman is a pediatric oncologist with research training and interest in cancer epidemiology, prevention and long-term health-related outcomes of therapy. Environment: The Fred Hutchinson Cancer Research Center (FHCRC), University of Washington (UW) and Children's Hospital and Regional Medical Center (CHRMC) comprise the Seattle Cancer Care Alliance (SCCA), which facilitates sharing of research resources. This research will be performed in the FHCRC Cancer Prevention Research Program under the mentorship of Dr. John Potter. Research Plan: The hypothesis to be tested is that genetic differences in the metabolism of chemotherapeutic agents, in the provision of nucleotides for DNA synthesis, and in DNA repair modify risk of SMN development. To address this hypothesis, we will examine allelic variants of genes involved in these processes in two well-defined cohorts at high risk of SMN. These are patients treated for childhood cancer with conventional therapy, and patients treated with hematopoietic stem cell transplant. The genes chosen for study include methylenetetrahydrofolate reductase (MTHFR), Glutathione-S-transferase (GST), GSTT1, GSTM1, GSTM3, GSTP1, Cytochrome P-450 (CYP) CYP2C9, CYP2C19, CYP3A4, thiopurine methyltransferase, methylguanine DNA methyltransferase, ERCC1, XPD, XRCC1, XRCC2, XRCC3, XRCC4 and XRCC5. Nested case-control methodology will be used, in each of the cohorts, to examine the association of specific allelic variants with SMN development. Career Plan and Development: Dr. Friedman's career goal is to be a translational researcher with a focus on cancer control, prevention, and long-term outcomes of therapy. This award will provide continued mentored training in molecular biology, cancer genetics and epidemiology and biostatistics. Educational opportunities will be provided to Dr. Friedman in the Division of Public Health Sciences at Fred Hutchinson Cancer Research center and in the School of Public Health at the University of Washington. The findings of this research can be applied to the development of preventive strategies of second malignant neoplasms and other adverse long-term health-related outcomes for cancer survivors.