Melanoma: Clinical Features and Genomic Insights

Abstract

Recent efforts in genomic research have enabled the characterization of molecular mechanisms underlying many types of cancers, ushering novel approaches for diagnosis and therapeutics. Melanoma is a molecularly heterogeneous disease, as many genetic alterations have been identified and the clinical features can vary. Although discoveries of frequent mutations including BRAF have already made clinically significant impact on patient care, there is a growing body of literature suggesting a role for additional mutations, driver and passenger types, in disease pathophysiology. Although some mutations have been strongly associated with clinical phenotypes of melanomas (such as physical distribution or morphologic subtype), the function or implications of many of the recently identified mutations remains less clear. The phenotypic and clinical impact of genomic mutations in melanoma remains a promising opportunity for progress in the care of melanoma patients. There have been many recent advances in our understanding of melanoma, from a greater appreciation of epidemiologic trends and risk factors to an increased understanding of the molecular genomics and biology of melanoma. Studies suggest that a number of molecularly distinct changes have a role in the pathophysiology of melanoma, and melanomas encompass a heterogeneous group when considering many known genomic alterations and diverse clinical phenotypes. To date, there are clinical subtypes or "phenotypes" of melanoma that are associated with specific genomic changes, in addition to many identified genomic mutations that lack a clear clinical correlation.Genomic studies are able to inform us about the disease phenotype, in addition to improving our understanding of disease pathogenesis. The various phenotypes of melanoma are characterized by clinical features, such as bodily distribution or risk factors. Cutaneous, uveal, acral, and mucosal melanomas (Fig. 1) have divergent clinical courses and are associated with distinct mutations, and risk factors such as skin phototype or UV exposure pattern are also associated with distinct alterations in genetic mutations. A melanoma phenotype can also be classified based on histopathologic morphology such as superficial spreading, nodular, desmoplastic, etc. In this review, we examine a number of Editors: Anthony E. Oro and Fiona M. Watt Additional Perspectives on The Skin and Its Diseases available at www.perspectivesinmedicine.org

Melanocytes and Their Diseases

“…Several melanoma susceptibility genes are related with genes responsible for pigmentation disorders including XP and LEOPARD syndrome. We refer readers to Hawryluk and Tsao (2014) for further information about melanoma. Of note, the gene expression profile of acral melanoma is dramatically different from the profiles of other types of melanoma (Curtin et al 2005).…”

Prognostic significance of L-type amino acid transporter 1 (LAT1) expression in cutaneous melanoma

“…Both the incidence and the prevalence of the disease have increased over the past few decades, whereas the overall mortality rates have remained somewhat stable [1]. As metastatic melanoma carries a poor prognosis, there is a need for novel therapies [2].…”

Bad company: Microenvironmentally mediated resistance to targeted therapy in melanoma

“…The transformation of melanocytes into melanoma requires a burden of mutations that can be initiated by exogenous and endogenous cues. Sporadic melanomas (approximately 90% of all melanoma cases) are frequently driven by low-to moderate-risk alleles that have high prevalence and low penetrance, indicating that environmental cues are key for malignant transformation (Chhabra et al, 2018;Eggermont, Spatz, & Robert, 2014;Hawryluk & Tsao, 2014;Schadendorf, Fisher, et al, 2015;Ward, Lazovich, & Hordinsky, 2012). Currently however, the pathway that has the highest oncogenic and therapeutic relevance in melanoma is the mitogen-activated protein kinase (MAPK) cascade, which is not attributable to direct UV damage (Hodis et al, 2012).…”