Recent advances in cutaneous melanoma: towards a molecular model and targeted treatment

Abstract

Melanoma is an aggressive disease process, with a heterogeneous aetiology linked to environmental and genetic risk factor profiles. Overall prognosis for advanced disease remains poor, and a lack of effective systemic therapies has prompted investigation into alternative strategies. The identification of novel mutations that instigate and perpetuate melanocyte transformation has offered insight into new treatment approaches, and the subsequent development of targeted treatments appears to be integral to improving melanoma survival. This article reviews the mechanisms of melanoma oncogenesis and classic molecular signalling pathways, targeted treatment approaches based on the molecular model and immunotherapy, and the advent of next-generation sequencing technologies in understanding the complexity of the melanoma pathogenome. In addition to the known somatic activating mutations BRAF and NRAS, exome sequencing has recently identified RAC1, a novel UV-signature gain-of-function mutation. Germline mutations associated with familial melanoma have added a further dimension to the molecular underpinnings of melanoma, implicating BAP1 and MITF as melanoma predisposition genes. Advances in understanding melanoma and implementing targeted treatment strategies will be of increasing importance in this era of personalised medicine.

Monitoring BRAF and NRAS mutations with cell-free circulating tumor DNA from metastatic melanoma patients

“…The survival of patients with metastatic melanoma has improved with treatment with BRAF and MEK inhibitors [ 1 ] or with immunotherapy such as anti-PD-1 or anti-CTLA-4 antibodies [ 2 , 3 ]. The mutated BRAF oncogene represents a therapeutic target in metastatic melanoma, where a mutated NRAS oncogene is a biomarker of poor outcome [ 4 ] and resistance to treatment with BRAF inhibitors [ 5 ].…”

LncRNA MEG3 promotes melanoma growth, metastasis and formation through modulating miR-21/E-cadherin axis

“…Melanoma is a cutaneous cancer caused by the malignant transformation of pigment-producing cells melanocytes located predominantly in the skin and characterized by high metastatic potentials [23]. Moreover, it is responsible for 75-80% of deaths from skin cancer and generally higher in fair-skinned population [24]. In recent years, there were still no satisfactory treatments to fight melanoma, especially for the advanced patients [25].…”

Diffuse melanosis cutis in the setting of BRAFV600E metastatic melanoma

“…It is being increasingly recognized that melanoma is not a single disease, rather that distinct molecular events underpin melanoma pathogenesis with the development of different melanoma subtypes. 4 While it is not known why some patients with metastatic melanoma develop DMC, it is plausible that there is a specific genotypic subtype of melanoma that lends itself to its development. A recently completed systematic review of DMC described the dismal prognosis associated with this condition with a mean survival of approximately four months from the onset of melanosis.…”