Melanoma Genomics: A State-of-the-Art Review of Practical Clinical Applications

S. Guhan; N. Klebanov; H. Tsao


The British Journal of Dermatology. 2021;185(2):272-281. 

In This Article

Abstract and Introduction


Our collective understanding of melanoma genomics has rapidly expanded in the past decade, bringing great promise to patients affected with the most severe and aggressive cases of melanoma. In this review, we present the practical clinical impact of genetics and genomics on modern melanoma diagnosis and treatment. Characterization of somatic driver mutations, which can be used to distinguish different subtypes of melanoma such as nonacral cutaneous melanoma (NACM), desmoplastic melanoma (DM), acral melanoma (AM), mucosal melanoma (MM) and uveal melanoma (UM), has led to the development of many targeted therapies against these tumours. Although targeted therapies exist for certain mutations, such as BRAF and KIT, other genotypes respond to newer-generation immune therapies such as immune checkpoint inhibitors. Epigenetics also plays a critical role in melanoma pathogenesis and drug resistance, holding promise for new treatment avenues. In this review, special attention is placed on clinical trials and translational research, especially novel genomic tests aimed to benefit patients on an individualized level in the current emerging era of personalized therapy.


Malignant melanoma has high morbidity and mortality rates if left untreated. In 2021 there will be an estimated 106 110 new case of patients with melanoma, with 7180 deaths in the USA.[1] Although the cases of melanoma continue to increase, the number of deaths has stabilized. This stabilization is the result, in part, of our increased understanding of melanoma pathogenesis and the mutations driving the development of disease. We are now better able to identify patients who have a hereditary predisposition for disease, and can appropriately screen their skin and other organs for associated cancers. Furthermore, there has been an explosion of therapeutics that are being successfully used to treat melanoma, such as immunotherapy and drugs targeted at specific melanoma drivers.

However, melanoma still has a poor prognosis for many patients. Targeted therapies for patients with the BRAFV600E mutation [e.g. with combination BRAF + mitogen-activated protein kinase kinase (MEK) inhibition] only confer an 11·1- to 14·9-month median progression-free survival and a 22·5- to 33·6-month median overall survival.[2–6] The most effective immunotherapy combination (nivolumab plus ipilimumab) has an approximately 50% 5-year survival rate.[7] This is due in part to the complexity of melanoma genetics, involving variable gene–gene interactions and various mechanisms of immune escape. Thus, despite our understanding of the various mutations and genes that drive melanoma, much more needs to be discovered in order to reduce melanoma fatalities.

In this review, we provide an overview of the somatic mutations and epigenetics that are associated with different types of melanoma and provide information about the impact of genetics on modern diagnosis and treatment.