Undergraduate Honors Theses

Thesis Defended

Spring 2017

Document Type

Thesis

Type of Thesis

Departmental Honors

Department

Biochemistry

First Advisor

Joseph Falke

Second Advisor

Robert Parson

Third Advisor

Jennifer Martin

Fourth Advisor

Natalie Ahn

Fifth Advisor

William Robinson

Abstract

Kinase gene fusions are a mechanism of alternative pathway activation and have been increasingly described in cancer, including malignant melanoma. The prevalence of kinase gene fusions across different subtypes in melanoma has not yet been reported. Additionally, few studies in melanoma have examined the responses of these kinase gene fusions to small molecule inhibitors. We used break-apart fluorescence in situ hybridization (FISH) to identify genomic rearrangements in tissues from 59 patients with various types of malignant melanoma including acral lentiginous, mucosal, superficial spreading, and nodular. We identified four genomic rearrangements involving the genes BRAF, RET, and ROS1. Of these, three were confirmed by immunohistochemistry (IHC) or sequencing. We identified a RET fusion in an acral lentiginous melanoma, an ARMC10-BRAF fusion in an unknown primary melanoma, and an AGK-BRAF fusion in a superficial spreading melanoma. This is the first report of a RET fusion in melanoma and the ARMC10-BRAF fusion has not been previously described in melanoma. These fusions occurred in different subtypes of melanoma but all in tumors lacking known driver mutations. We went on to generate patient-derived xenograft (PDX) models of both BRAF fusions to show that both the ARMC10-BRAF and AGK-BRAF kinase fusions are sensitive to downstream mitogen-activated protein (MAP) kinase pathway inhibition. We characterized these responses and identified differential responses between the different BRAF gene fusions. Our data suggests gene fusions are more common than previously thought and are actionable therapeutic targets. Broader screening for kinase fusions in melanomas lacking known driver mutations should become part of routine clinical practice.

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