Morphogenetic Correlates and Mutations in Melanoma

• In addition to the classical descriptions of melanomas:
  • The ability to perform molecular profiling on tumors has added to our understanding of this complex and often heterogeneous disease
• Although currently not generally reported as part of the primary staging of melanoma:
  • Genetic profiling has been widely employed in advanced disease
    • With advances in technology, mutational analysis is routinely performed from formalin-fixed paraffin-embedded archival tissue
  • This has led to new insights into the pathogenesis of this disease as well as actionable treatment strategies against specific molecular aberrations, especially in the setting of unresectable and advanced disease
  • Recent studies demonstrate that most melanomas have one or more mutations in essential kinase signaling pathways
• Important in melanoma is the:
  • RAS-RAF-MEK-ERK kinase-signaling pathway
• Studies have consistently found that 40% to 50% of cutaneous melanomas (particularly superficial spreading melanoma):
  • Harbor mutations in a particular member of the RAF family known as BRAF
    • Although multiple BRAF mutations have been identified:
      • Approximately 90% consist of a point mutation at V600E that leads to an approximately 400-fold increase in the activity of the BRAF protein
    • Interestingly, 70% to 80% of benign nevi also harbor BRAF mutations:
      • Suggesting that genetic alterations alone cannot fully explain the aggressive biology of melanoma
  • In the same kinase pathway, approximately 15% to 26% of melanomas:
    • Are found to have an activating NRAS mutation
  • A comprehensive molecular analysis of cutaneous melanoma by The Cancer Genome Atlas (TCGA) melanoma project has provided new insights into the roles and frequency of mutated cancer genes and other genomic signatures
  • These findings helped to establish that cutaneous melanoma can be grouped into one of four subtypes:
    • BRAF mutant (most common)
    • RAS mutant
    • NF1 mutant
    • Triple-WT (wild type)
  • Interestingly, BRAF and NRAS mutations:
    • Are rarely identified simultaneously in the same melanoma tumor
• The phosphatase and tensin homolog (PTEN) protein is widely expressed throughout the human body:
  • PTEN acts as a phosphatase to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate
  • The PI3 kinase-AKT pathway:
    • Is the most common kinase pathway mutated in cancer
  • PTEN inhibits the activation of AKT:
    • Therefore, loss of PTEN results:
      • In the constitutive activation of the AKT pathway
  • Often, PTEN loss is found concurrently with NRAS mutations
  • Mutations in AKT have also been identified in melanoma
• While MAP kinase signaling pathway mutations:
  • Have been commonly found in cutaneous melanomas arising in sun-exposed areas:
    • They are infrequent in mucosal and acral lentiginous melanomas
• A missense mutation in the c-KIT gene:
  • Has been found in more than 20% of mucosal melanomas and more than 10% of acral lentiginous melanomas

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