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Toward a Molecular Classification of Melanoma

Leslie A. Fecher, Staci D. Cummings, Megan J. Keefe, Rhoda M. Alani

From the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; and the Departments of Oncology and Pharmacology and Molecular Sciences, Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD

Address reprint requests to Rhoda M. Alani, MD, Johns Hopkins University School of Medicine, 1650 Orleans St, CRB 342, Baltimore, MD 21231-1000; e-mail: ralani{at}jhmi.edu

The incidence of melanoma is increasing at one of the highest rates of any form of cancer in the United States, with the current lifetime risk being one in 68. At present, there are limited systemic therapies to treat advanced stages of melanoma, and the key to improved survival remains early detection. Recent discoveries have allowed for a clearer picture of the molecular events leading to melanoma development and progression. Since identifying prevalent activating mutations of the BRAF kinase in melanomas, there has been a flood of additional molecular studies to further clarify the role of this pathway and others in melanomagenesis. In particular, recent genetic studies have demonstrated specific genotype-phenotype correlations that provide the first major insights into the molecular subclassification of melanoma and the heterogeneous nature of this malignancy. In this article, we review the most up-to-date molecular discoveries in melanoma biology and provide a framework for understanding their significance in melanoma development and progression. We also provide details on the development of novel therapies based on these recent molecular discoveries and insight into current and planned clinical trials. It is expected that these latest studies in melanoma will help define the critical molecular events involved in disease onset and progression and allow us to move rapidly toward a true molecular classification. We eagerly anticipate rationally designed melanoma therapies based on such a classification scheme and the associated improvements in patient outcomes.

Supported by Grant No. CA107017 from the National Cancer Institute, the Flight Attendant Medical Research Institute, and the Joanna M. Nicolay Melanoma Foundation.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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