Melanoma is the deadliest skin cancer and is responsible for nearly 60,000 deaths worldwide each year. At least some melanomas are believed to arise from stepwise progression from normal melanocytes through a benign nevus stage to malignant melanoma and finally metastatic disease. Approximately 20–50% of melanomas have evidence of a pre-existing nevus, indicating that progression is an important route of melanomagenesis. Ultraviolet radiation exposure is believed to play an important role in nevus and melanoma formation, although the mechanisms of this remain unclear. Childhood sunburn and intermittent sun exposure are epidemiologically linked to increased melanoma risk. While most melanomas have activation of the mitogen activated protein kinase pathway, often due to mutations in BRAF or RAS genes, nearly 15% of cutaneous melanomas do not have an identified strong driver. Despite targeted therapies and immunotherapy, the death rate from melanoma has remained nearly static for several decades, so there is a need to identify additional genes and pathways to provide novel therapeutic targets. We hypothesized that progression of melanocytic lesions from benign to malignant is associated with the acquisition of additional genomic mutations. Unlike wildtype mice, hepatocyte growth factor (HGF) transgenic mice have “humanized” distribution of melanocytes along the dermal-epidermal junction. Following a single dose of UV at 3 days of age, HGF mice develop melanocytic nevi and melanomas. In this project, two HGF models were used to generate melanocytic lesions. The first model, on an albino FVB background had a tumor incidence of only 10% and used melanocyte-specific green fluorescent protein expression to identify early nevi and melanomas. The second model, on a C57BL/6 had a high tumor incidence (80%), and 60% of tumor-bearing mice have metastatic lesions. Sequencing of melanocytic lesions at different stages revealed a variety of driver mutations, including Nf1, Gnaq, and Gna11, as well as genes and pathways with less established roles in melanoma development. Our data provide a broad overview of genes and pathways involved in progression of non-BRAF, non-NRAS melanoma. Additionally, we present the first potential germline variants that may increase metastatic susceptibility for melanoma patients. These genes suggest potential biomarkers for progression of melanocytic lesions.
|Advisor:||Samal, Siba, Merlino, Glenn|
|Commitee:||Merlino, Glenn, Mosser, David, Samal, Siba, Simpson, R. Mark, Zhu, Xiaoping|
|School:||University of Maryland, College Park|
|Department:||Veterinary Medical Science|
|School Location:||United States -- Maryland|
|Source:||DAI-B 80/07(E), Dissertation Abstracts International|
|Subjects:||Genetics, Histology, Oncology|
|Keywords:||GNAQ, Melanoma, Mouse models|
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