Toward a Molecular Classification of Melanoma

Abstract

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.

Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma

“…3 Although linked to exposure to ultraviolet light, it is widely accepted that both genotypic and phenotypic changes in melanocytes predispose to melanocyte transformation and the onset of melanoma. 4,5 Surprisingly, p53 mutations are very rare in melanoma, but activity is, however, impaired through direct or indirect inactivation of key elements of this pathway, including through the suppression of APAF-1 expression, 6 loss of PTEN function, 7 dysregulation of Bcl-2 expression, 8 upregulation of the anti-apoptotic protein Mcl-1 together with its altered slice variant expression 9,10 and the ER chaperone GRP78. [11][12][13] Oncogenic mutations, however, in the Ras/Raf pathway are the most well-described genetic mutations associated with melanoma development and progression.…”

Mutant IDH1 Confers an in Vivo Growth in a Melanoma Cell Line with BRAF Mutation

“…6 Recent genetic investigations have also demonstrated specific genotype-phenotype correlations that would be potentially informative in the context of the molecular subclassification of melanoma and therapeutic target molecules. 7 For example, the c-kit gene mutations have been frequently reported in acral lentiginous/mucosal melanomas and are associated with better responsiveness to the inhibitor, imatinib. 8 -10 Recently, unbiased whole-exon resequencing analysis of glioblastoma multiforme has revealed recurrent mutation of the two IDH (isocitrate dehydrogenase) isoforms, IDH1 and IDH2.…”

Streamlining Molecular Pathobiology of Malignant Melanoma

“…As each probe has a unique length due to its stuffer sequence, electrophoresis points to the amount of PCR product related to the DNA copy number. Mutation-specific MLPA combines copy number detection and hot-spot mutations in a single assessment 8 . Different CMM types are possibly distinguished [73].…”

“…Over recent decades, CMM immunopathology shifted the diagnosis process from descriptive morphology to more accurate information focusing on neoplastic cell phenotype and proliferation rate [4 -6]. Currently, immunopathology helps distinguishing among a set of atypical melanocytic neoplasms, and supports attempts to precise CMM staging [4][5][6][7][8][9][10][11]. The aspect of the peritumoral stroma is moreover informative [12,13] .…”