Genetic risk factors of pediatric germ cell tumors and the late effects of their treatment
2021-09
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Genetic risk factors of pediatric germ cell tumors and the late effects of their treatment
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2021-09
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Pediatric germ cell tumors (GCTs) are a heterogeneous group of tumors and their etiology is poorly understood. There are distinct differences between GCTs that arise in early childhood and those in adolescents and young adults, but recent studies of GCTs implicate genetics in the etiology of disease across all age groups. In Manuscript 1, we interrogated the genetically regulated expression of genes within the cell cycle control or apoptosis cellular pathways for their role in pediatric GCT risk. Our results suggest a previously identified association with an intronic variant near BAK1, a pro-apoptotic gene, may be acting through the reduced expression of BAK1. Hispanic children have the highest risk of pediatric GCTs overall, although incidence rates by race/ethnicity do vary by tumor location, sex, and age at diagnosis. No risk factors have been identified to date to explain the excess risk in Hispanic children and in countries in Central America. In Manuscript 2, we employed admixture mapping methods to interrogate genomic regions specific to Hispanic admixture to explore genetic loci contributing to the excess risk in GCTs among Hispanic children. We did not find any genetic loci that reached our threshold for statistical significance, but Amerindian ancestry regions on chromosome 7 were overrepresented among our top results and may warrant further exploration in a sample greater powered for subgroup analyses.
Pediatric GCT survival has approached 90% due to the success of platinum-based therapies, but there are substantial late effects of treatment. Little is known about the burden of late effects in pediatric GCT survivors, as they were excluded from the Childhood Cancer Survivor Study. However, pediatric GCT survivors comprise the third largest group of pediatric cancer survivors in the United States. Platinum-based chemotherapy is a risk factor for chemotherapy-induced peripheral neuropathy (CIPN), which is a progressive, debilitating condition with significant effects on a survivor’s quality of life. In Manuscript 3, we characterized the prevalence of CIPN in pediatric GCT survivors and explored the genetic susceptibility to CIPN in survivors that received platinum-based chemotherapy. We found that 24% of our pediatric GCT survivors had at least two symptoms of CIPN after an average of 9 years following their diagnosis. Our genetic studies did not identify genetic risk factors although power was limited to detect variants that reached genome-wide significance.
Overall, our first project provided information related to the functional significance of a previously identified variant, our second manuscript is the first genetic study in any age group to include cases of non-European ancestry and our final manuscript is the first study of CIPN in the pediatric age group.
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University of Minnesota Ph.D. dissertation. September 2021. Major: Epidemiology. Advisor: Jenny Poynter. 1 computer file (PDF); ix, 113 pages.
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Hubbard, Aubrey. (2021). Genetic risk factors of pediatric germ cell tumors and the late effects of their treatment. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/225115.
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