Biomedical Sciences ETDs

Publication Date

12-1-2015

Abstract

Skin cancer is the one of the most diagnosed cancers in the United States with increasing incidence of 6% every year. In 2015, it is estimated 73,870 new cases of melanoma will be identified and 9,480 individuals will die of their disease. While melanoma only accounts for approximately 2.4% of all cancer related deaths and is the 5th leading diagnosed cancer (US) it is the one of the most common cancers in young adults, age 25-29, particularly for young women. Of particular importance, the mean survival rate of patients diagnosed with metastatic melanoma is six months, with five-year survival rates of less than 5%. One reason for the increasing incidence in young adults may be due to the use of indoor tanning. UV exposure causes DNA damage and can induce the activation of a metabolic pathway called autophagy. Autophagy is activated by stress, including DNA damage, and melanoma risk is associated with UV exposure. Here I present three studies investigating oncogene differences in rates of autophagy as well as the relationship of UV exposure and genotypic variants to autophagy. In this project, I determine whether oncogene status in melanoma differentially regulates apoptosis by modifying autophagic flux. The central hypothesis of this project is that cutaneous malignant melanomas (CMM) with BRAF mutations may be autophagy-addicted while tumors with NRAS mutations may be less dependent on autophagy. I found that BRAF/NRAS mutations differentially alter autophagic flux to suppress apoptosis in melanoma. Our results show that oncogene status in melanoma correlates with differential regulation of autophagic flux and that inhibition of autophagy in BRAF mutant melanoma cells results in apoptosis. These data suggest that BRAF mutant melanoma cells suppress apoptosis by modifying autophagic flux and that these cells may be autophagy addicted in order to promote survival. I also determined that proxy autophagy markers LC3 and Beclin1 are associated with UV exposure and clinical stage when evaluating tissue sections from melanoma patients and controls. Surprisingly, the NRAS wide-type sections had elevated LC3 levels when compared to the NRAS mutant tissue sections suggesting that autophagy may be inhibited NRAS in melanoma tumors. These results indicate that autophagic flux varies by tumor stage and is associated with UVR exposure. Finally, I also determined that several SNPs in autophagy-related genes are melanoma prognostic indictors. Of note, one SNP that has previously been shown to be inversely associated with other diseases, with a functional variant which increases disease susceptibility, was inversely associated with Breslow thickness, the most important indicator of melanoma outcome. The work from my study helps address the inconsistencies in the literature regarding autophagy's impact on melanoma progression. Furthermore, these studies provide a basis to investigate the roles of ATG gene SNPs, UV exposure and utophagy in melanoma.

Keywords

Autophagy, melanoma, oncogenes

Sponsors

National Cancer Institute

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Berwick, Marianne

First Committee Member (Chair)

Hu, Chien-An A.

Second Committee Member

Thompson, Todd

Third Committee Member

Hathaway, Helen

Available for download on Thursday, December 14, 2017

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