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SARCOMA DEVELOPMENT IN THE RADIATION LATE EFFECTS COHORT OF RHESUS MACAQUES (MACACA MULATTA)

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title
SARCOMA DEVELOPMENT IN THE RADIATION LATE EFFECTS COHORT OF RHESUS MACAQUES (MACACA MULATTA)
author
Sills, William Shane
abstract
Radiation exposure is a severe risk cancer. A robust animal model to accurately recapitulate human disease is important for mechanistic studies, drug discovery, and pre-clinical trials. At Wake Forest School of Medicine, we have a unique resource: the Radiation Late Effects Cohort (RLEC) of rhesus macaques (Macaca mulatta). These are recruited into the cohort from various institutions after completion of acute, total-body irradiation studies, and monitored for long-term disease manifestation, and includes non-irradiated controls. Since 2007, our group has documented chronic health issues in these monkeys, years after exposure, including cancer. This dissertation leverages the RLEC as a model for radiation-induced cancer. We first enumerated neoplasms in this cohort, and established a hazard ratio of cancer in the irradiated animals. Unlike what is expected in normal, aging macaques, the RLEC monkeys are prone to mesenchymal tumors. RLEC macaques acquired cancer at a younger age than what is expected in non-irradiated monkeys. Irradiated animals had neoplasia at double the expected incidence. We only observed a single cancer in the non-irradiated controls. Irradiated monkeys had a 23-fold hazard ratio of developing cancer over non-irradiated. We next investigated RLEC sarcomas with whole exome sequencing (WES). RLEC sarcomas had increased C-to-T and G-to-A transitions and a high proportion of INDELs, most of which were deletions. We found mutations in several COSMIC genes, particularly TP53. Mutated genes in sarcomas were frequently present in pathways associated with apoptosis, senescence, and cell cycle regulation. RNA sequencing comparing normal macaque dermis to RLEC dermal sarcomas revealed up-regulation of genes associated with extracellular matrix and humoral immune responses in the sarcomas. Lastly, we focused on RLEC glomus tumors, the second-most common sarcoma in the RLEC. These are otherwise very rare in monkeys. Histological features were consistent with expected phenotypes in humans, were generally low-grade, but had some features of malignancy. Mutational features resembled other sarcomas of the cohort. Glomus tumors showed aberrant p53 protein expression, despite lacking TP53 mutations. The RLEC is a valuable resource for studying radiation-induced sarcomas, as they have many overlapping features with human sarcomas.
subject
cancer pathology
carcinogenesis
genomics
non-human primate
radiation
sarcoma
contributor
Cline, J Mark (advisor)
Grayson, Jason M (committee member)
Hawkins, Gregory A (committee member)
Langefeld, Carl D (committee member)
Soto-Pantoja, David R (committee member)
date
2023-09-08T08:35:27Z (accessioned)
2023 (issued)
degree
Molecular Medicine and Translational Science (discipline)
embargo
2024-09-07 (terms)
2024-09-07 (liftdate)
identifier
http://hdl.handle.net/10339/102620 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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