This proposal will use an innovative approach to identify previously unknown genes involved in melanoma progression that are potentially important for personalized therapies. Melanoma is the most aggressive form of skin cancer and impacts 1 in 50 Americans. Moreover, melanoma is one of the only cancers whose incidence has increased in recent years, showing a 6-fold increase in diagnosed cases over the past 40 years, with especially high risk in young men. Developing effective treatments for melanoma starts with understanding its underlying genetic causes. Recent efforts have identified common genetic mutations that drive the formation of cancers. However, individual patients with the same ge...

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This proposal will use an innovative approach to identify previously unknown genes involved in melanoma progression that are potentially important for personalized therapies. Melanoma is the most aggressive form of skin cancer and impacts 1 in 50 Americans. Moreover, melanoma is one of the only cancers whose incidence has increased in recent years, showing a 6-fold increase in diagnosed cases over the past 40 years, with especially high risk in young men. Developing effective treatments for melanoma starts with understanding its underlying genetic causes. Recent efforts have identified common genetic mutations that drive the formation of cancers. However, individual patients with the same genetic "driver" mutations contributing to cancer development often show variation in the progression of the disease and in their responses to normally applied treatments. In spite of apparently similar risk factors, these distinct responses are likely due to the presence of cryptic tumor modifier genes that interact with melanoma "driver" genes and alter the disease trajectory. Unfortunately, such tumor modifier genes have been extremely difficult to identify, with only a handful discovered to date. Thus, there are important genetic and clinical implications of identifying new tumor modifier genes and characterize their actions. Swordtail fish, like humans, naturally develop melanoma. Notably, specific populations have been shown to develop melanoma at an extremely high rate. These pigment cell lesions vary individually from small spots to highly malignant melanoma. We will look for stretches of DNA that predict whether or not a fish will develop melanoma and whether this will melanoma will further develop into a fatal cancer. We will then use established lab techniques to test the precise roles of these genes' in cancer pathways at the molecular level, ultimately contributing to better understanding, diagnosis, and treatment of human melanoma.

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