Melanoma

Abstract

Melanoma is a lethal skin cancer that has steadily risen in incidence over the past five decades. Tumours exhibit high rates of somatic mutation largely attributable to UV mutagenesis. Historically, patients diagnosed with advanced melanoma had a poor prognosis. However, the development of targeted therapies for BRAFV600‐mutant melanoma and immunotherapies that block immune checkpoints has substantially improved patient outcomes. Although MAPK pathway inhibitors and immunotherapies have transformed melanoma treatment, substantial challenges persist. These include overcoming resistance to targeted agents, developing targeted therapies for genetic subtypes beyond BRAFV600‐mutant melanoma and enhancing response rates to immunotherapy.

Key Concepts

  • Cutaneous melanoma (CM) is a lethal form of skin cancer that originates from pigment‐producing melanocytes.
  • UV exposure is the primary environmental risk factor for sporadic melanoma development, driving extremely high rates of somatic mutation.
  • Germ‐line variants that increase melanoma susceptibility typically modulate pigmentation and density.
  • The predominant genetic subtypes of CM (BRAFmut, NRASmut and NF1mut) share a common dependence on deregulated MAPK pathway signalling.
  • Other signalling pathways frequently deregulated include PI3K/AKT, CDKN2A and p53.
  • TERT promoter mutations are present in most melanomas, enabling telomerase reactivation, deregulating telomere maintenance and promoting immortalisation.
  • Targeted therapies that inhibit MAPK signalling can elicit profound tumour regression in patients with advanced BRAFV600‐mutant melanoma; however, resistance typically develops and patients relapse within 1–2 years.
  • Immune checkpoint blockade elicits long‐term responses in a small subset of patients.
  • Combinations of targeted agents and immunotherapies are being evaluated to provoke more durable responses.

Keywords: melanoma; skin neoplasms; risk factors; genetics; mutation; pathogenesis; signal transduction; targeted therapy; immunotherapy

Figure 1. Model of melanoma progression. Melanoma subtypes display distinct evolutionary trajectories. Melanomas arising on nonchronically sun damaged (non‐CSD) skin commonly harbour the BRAFV600E mutation, which is found in benign precursor lesions (naevi). Non‐V600E BRAF, NRAS and NF1 mutations are associated with chronic sun damage (CSD) and may be identified in dysplastic intermediate lesions. Mutations that reactivate TERT expression are identified early in melanoma progression. Loss‐of‐function alterations in CDKN2A and SWI/SNF family members are selected for later in melanomagenesis, at the transition to invasion. PTEN or TP53 inactivation emerges in advanced invasive melanomas. PTEN is more commonly inactivated in BRAFV600E melanomas, whereas TP53 is more frequently inactivated in NRASmut and NF1mut melanomas (Cancer Genome Atlas Network, ).
Figure 2. Signalling pathways deregulated in melanoma. Signalling pathways that control cellular growth, proliferation and survival are deregulated in melanoma. Genetic alterations to components of the MAPK/ERK, PI3K/AKT, CDKN2A and p53 pathways promote melanoma initiation and progression. Activating mutations to GNAQ or GNA11 are the primary oncogenic lesions in uveal melanoma, whereas BRAF, NRAS or NF1 mutations are the most frequent drivers of cutaneous melanoma. Telomerase expression is reactivated in most melanomas via TERT promoter mutations generating de novo ETS transcription factor‐binding sites. MITF acts as a lineage‐specific oncogene that is amplified or mutated in a subset of melanomas.
Figure 3. Timeline of FDA‐approved drugs for advanced melanoma. Since the introduction of ipilimumab (anti‐CTLA‐4) in 2011, the number of drugs approved for treatment of metastatic melanoma has expanded dramatically. These include targeted therapies directed against the MAPK signalling pathway and immunotherapies. Several drugs originally approved as monotherapies are now available as combinations which elicit greater clinical benefits.
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Further Reading

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Guterres, Adam N, Herlyn, Meenhard, and Villanueva, Jessie(Jul 2018) Melanoma. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001894.pub3]