The Somatic Genetics of Human Melanoma
CitationHodis, Eran. 2018. The Somatic Genetics of Human Melanoma. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractHow do you make a melanoma? Which mutations of the genome turn a normal melanocyte residing at the base of the epidermis into a malignant cancer? And what commonalities unite the myriad genetic paths to melanoma into broad requirements for melanoma pathogenesis?
The research herein, into the pathogenesis of melanoma, has been enabled by two new technologies. Next-generation sequencing first allowed an unbiased ascertainment of the genetic changes in patient-derived human melanomas, leading to discovery of several mutated melanoma genes. CRISPR/Cas9 genome editing then enabled a retracing of the pathogenesis of melanoma through the introduction of precise mutations into primary human melanocytes to create metastatic melanoma cells.
Chapter 1 reviews current knowledge of the somatic genetics of all types of melanocytic neoplasia, though the rest of this thesis focuses exclusively on melanoma of hair-bearing skin. Chapter 2 presents an analysis of the whole-genome sequences of twenty-five melanomas, highlighting the mutated gene PREX2. Analysis of these whole-genome sequences led to the identification of highly recurrent mutations in the promoter sequence of TERT, and Chapter 3 focuses entirely on those mutations. Chapter 4 next delves into the somatic coding mutations of melanoma by analysis of over one hundred melanoma exome sequences, defining common mutation patterns. Finally, Chapter 5 introduces the use of genome editing of primary human melanocytes to establish causal relationships between sets of genetic mutations and phenotypes of malignancy.
Through characterization of the melanoma genome and subsequent study of melanoma mutations in an experimental model, this thesis has endeavored to further understanding of human melanoma pathogenesis and to put forward answers to the basic question, “How do you make a melanoma?”
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41129208
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