Genomic and Transcriptomic Underpinnings of Melanoma Genesis, Progression, and Metastasis

Simple Summary Melanoma is a skin cancer with a high mortality and a dramatically rising presence worldwide. Recent research has shed new light on the genetic events that promote melanoma progression and confer metastatic potential. This review summarizes the role of molecular pathways, genomic factors, and the tumor microenvironment in the progression from local melanoma to distant disease. Further characterization of these elements is necessary to identify relevant prognostic factors and potential new therapeutic targets. Melanoma is a deadly skin cancer with rapidly increasing incidence worldwide. The discovery of the genetic drivers of melanomagenesis in the last decade has led the World Health Organization to reclassify melanoma subtypes by their molecular pathways rather than traditional clinical and histopathologic features. Despite this significant advance, the genomic and transcriptomic drivers of metastatic progression are less well characterized. This review describes the known molecular pathways of cutaneous and uveal melanoma progression, highlights recently identified pathways and mediators of metastasis, and touches on the influence of the tumor microenvironment on metastatic progression and treatment resistance. While targeted therapies and immune checkpoint blockade have significantly aided in the treatment of advanced disease, acquired drug resistance remains an unfortunately common problem, and there is still a great need to identify potential prognostic markers and novel therapeutic targets to aid in such cases.