Molecular Profiling of Melanoma

Melanoma is a malignant tumor of melanocytes. The disease is the fifth most common cancer in men and the seventh in women with an estimated 76,100 new cases and 9,710 deaths in 2014 in the U.S. (ACS 2014). Melanoma is treated with a combination of surgery, traditional cytotoxic chemotherapy, targeted therapies, and immune-based therapies. Five-year survival rates for patients with metastatic disease, unfortunately, are below 10% (Jemal et al. 2010). Novel therapies and treatment strategies are needed.

Historically, melanoma has been classified according to pathologic and clinical characteristics such as histology (depth, Clark level, ulceration) and anatomic site of origin. Over the past decade, it has become evident that subsets of melanoma can be further defined at the molecular level by recurrent "driver" mutations that occur in multiple oncogenes, including BRAF, GNA11, GNAQ, KIT, MEK1 (MAP2K1), and NRAS (Table 1; Figure 1). Such driver mutations lead to constitutive activation of mutant signaling proteins that induce and sustain tumorigenesis.

Mutations in BRAF, GNA11, GNAQ, KITMEK1 (MAP2K1), and NRAS can be found in approximately 70% of all melanomas. In addition, mutations in CTNNB1 have also been described in melanoma. Mutations in more than one of these genes are seldom found concurrently in the same tumor. The distribution of mutations varies by site of origin and also by the absence or presence of chronic sun damage (Table 1; Figure 1). Importantly, targeted small molecule inhibitors are currently available or are being developed for specific molecular subsets of patients with melanoma.

The mutation-specific pages are meant to provide a broad overview of several of the oncogenes known to be important for melanoma pathogenesis. Where possible, the presence of a specific mutation is correlated to clinical parameters as well as response to both conventional chemotherapy and targeted agents. At present, only data for treatment of advanced (stage IV) disease are presented.

Table 1. Frequency of Somatic Gene Mutations in Melanoma.

Mutated Gene Frequency in Melanoma
BRAF ~50% (COSMICDavies et al. 2002Maldonado et al. 2003)​​
CTNNB1 ~2–3% (Demunter et al. 2002Omholt et al. 2001Pollock and Hayward 2002Reifenberger et al. 2002Rimm et al. 1999)​
KIT ~2–6% (Beadling et al. 2008; Curtin et al. 2006; Handolias et al. 2010; Willmore-Payne et al. 2005)
MEK1 6% (Nikolaev et al. 2012)
NRAS​ ~13–25% (Ball et al. 1994; Curtin et al. 2005; van 't Veer et al. 1989)


Figure 1.
Molecular subsets of melanoma. Depicted is the frequency of driver mutations in melanoma related to anatomic location of the primary tumor. Frequencies of MEK1 and CTNNB1 mutations according to anatomic location are not known at present.​​​​​​​​

Contributors: Christine M. Lovly, M.D., Ph.D., William Pao, M.D., Ph.D. (through April 2014), Jeff Sosman, M.D.

Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2014. Molecular Profiling of Melanoma. My Cancer Genome (Updated August 8).

Last Updated: August 8, 2014

Disclaimer: The information presented at is compiled from sources believed to be reliable. Extensive efforts have been made to make this information as accurate and as up-to-date as possible. However, the accuracy and completeness of this information cannot be guaranteed. Despite our best efforts, this information may contain typographical errors and omissions. The contents are to be used only as a guide, and health care providers should employ sound clinical judgment in interpreting this information for individual patient care.