| With recent rapid advances in high-throughput genomic technologies, we are now able to affordably interrogate entire genomes and epigenomes of ever-larger cohorts of both malignant and benign tissue samples. The resulting datasets are vast, necessitating innovative analytical approaches in order to glean biological meaning from the raw molecular-level data. In this dissertation, we focus on translational applications of these evolving genomic technologies for assessment of the human genome at baseline, in abnormal yet benign tissue, and in melanoma. Particular emphasis is placed on applications in epigenetics, specifically genome-wide DNA methylation patterns.;Recognition of the importance of epigenetic silencing in tumor biology has led to exploration of the therapeutic potential of demethylating agents in many cancers, melanoma among them. It is unclear why such agents cause some silenced loci to re-express, while others remain inactive. Using microarray-based assays to interrogate both promoter methylation and gene expression across multiple melanoma samples, we explore the effects of demethylating treatment on expression across the genome, identifying promoter characteristics that predict susceptibility to the treatment.;In order to expand the scope of interrogation beyond the genomic regions commonly present on microarrays, we next combine a methylation-enrichment assay with a high-throughput sequencing approach in order to describe the melanoma methylome with increased depth, breadth, and resolution. We include a detailed description of the melanoma methylome, comparing it to that of benign melanocytes from normal skin as well as from nevi, and identify distinct patterns of methylation among the tissue types. Combining the methylation data with whole-transcriptome sequencing data from the same samples, we relate methylation to transcription levels, and based on this integrated data we identify candidate biomarkers with the potential to distinguish melanoma from normal melanocytes.;We conclude with a discussion of the current state of melanoma diagnostics and treatment. In particular, we explore directed therapies such as specific inhibition of the mutated BRAF kinase, emphasizing the potential efficacy of treatment tailored to the individual patient on the basis of the tumor's molecular characteristics. The development of specific kinase inhibitors represents one of the few success stories in the past decades of melanoma oncology. Using high-resolution molecular level data, it is our hope that we will identify additional tumor characteristics that might serve either as biomarkers with clinical utility, or as targets for the type of individualized, directed therapy that will define the future of melanoma treatment. |
