UVM Theses and Dissertations
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Author:
Hathaway, Julie Ann
Dept./Program:
Microbiology and Molecular Genetics
Year:
2009
Degree:
PhD
Abstract:
Hodgkin's lymphoma is one of the most common childhood cancers in the 15- to 19-year age group. Although cure rates are among the highest for pediatric cancers, the treatment of Hodgkin's lymphoma may predispose patients to more aggressive, secondary hematologic malignancies and solid tumors. Despite this, the association between exposure to genotoxic therapies and genetic changes that may lead to the development of secondary neoplastic transformation in patients treated for Hodgkin's lymphoma is still unclear. Our study was done in collaboration with the Children's Oncology Group (COG). In an effort to improve the outcome and reduce the delayed effects of treatment in children and young adults with intermediate risk Hodgkin's lymphoma, the COG devised a unique protocol with response-based augmentation or reduction in therapy that allowed us the opportunity to examine and compare the mutagenic effects of different treatment approaches.
The first objective of our study was to investigate the mutagenic effects of treatment by determining the frequency of somatic mutations (Mfs) in peripheral T cells prior to, immediately following, and 1-year after the completion of therapeutic intervention. We determined the in vivo somatic mutation frequency using the hypoxanthine phosphoribosyl transferase (HPRT) T cell cloning assay for 265 peripheral blood samples from 179 subjects with Hodgkin's lymphoma. Overall we observed that HPRT Mf was significantly higher at all phases of treatment compared to Diagnosis. HPRT Mf increased with chemotherapy, peaked at the End of radiation therapy, declined at 1 -year off therapy, but not quite down to the levels found at Diagnosis. These findings suggest that while mutational load increases with treatment, especially with radiation therapy, the mutational load did not appear to be sustained after treatment.
The second objective focused on understanding the specific mutagenic mechanisms responsible for the somatic mutations observed in order to provide insight into the genetic risk for developing secondary malignancies following treatment. Longitudinal mutational spectral analysis at the HPRT locus was done on 722 mutants processed through the HPRT T cell cloning assay. Our analysis revealed unique changes in HPRT mutation spectra following treatment that included a significant increase in deletions, and in combined losses and duplications. These changes may contribute to the increased risk of second malignant neoplasms in these subjects following therapeutic intervention.
The first objective of our study was to investigate the mutagenic effects of treatment by determining the frequency of somatic mutations (Mfs) in peripheral T cells prior to, immediately following, and 1-year after the completion of therapeutic intervention. We determined the in vivo somatic mutation frequency using the hypoxanthine phosphoribosyl transferase (HPRT) T cell cloning assay for 265 peripheral blood samples from 179 subjects with Hodgkin's lymphoma. Overall we observed that HPRT Mf was significantly higher at all phases of treatment compared to Diagnosis. HPRT Mf increased with chemotherapy, peaked at the End of radiation therapy, declined at 1 -year off therapy, but not quite down to the levels found at Diagnosis. These findings suggest that while mutational load increases with treatment, especially with radiation therapy, the mutational load did not appear to be sustained after treatment.
The second objective focused on understanding the specific mutagenic mechanisms responsible for the somatic mutations observed in order to provide insight into the genetic risk for developing secondary malignancies following treatment. Longitudinal mutational spectral analysis at the HPRT locus was done on 722 mutants processed through the HPRT T cell cloning assay. Our analysis revealed unique changes in HPRT mutation spectra following treatment that included a significant increase in deletions, and in combined losses and duplications. These changes may contribute to the increased risk of second malignant neoplasms in these subjects following therapeutic intervention.