RAS and RAF mutations in banal melanocytic aggregates contiguous with primary cutaneous melanoma: clues to melanomagenesis

Br J Dermatol. 2009 Feb;160(2):368-75. doi: 10.1111/j.1365-2133.2008.08887.x. Epub 2008 Oct 20.


Background: Distinguishing banal melanocytic aggregates contiguous with malignant melanoma can be a histological challenge but is essential because of the potential for a spurious Breslow measurement.

Objectives: Our aim was to ascertain whether the histological distinction between the two relates to differences in the prevalence of mutations in genes significant in melanomagenesis.

Methods: Mutations in BRAF codon 600, NRAS1 codons 12/13, NRAS2 codons 60/61 and KRAS codons 12/13 were ascertained in 18 cases of primary cutaneous malignant melanoma contiguous with banal melanocytic aggregates using laser capture microdissection.

Results: Overall, 12 of 18 cases (67%) exhibited a mutation in at least one gene. BRAF V600E appeared to be the most commonly mutated gene in both the melanocytic aggregate (seven of 18, 39%) and the melanoma (four of 18, 22%). Both populations demonstrated a similar BRAF genomic profile in 11 of 18 cases (61%) (two BRAF V600E, nine BRAF-WT), a similar KRAS genomic profile in 14 of 18 cases (78%) (one KRAS G12V, 13 KRAS-WT) and a similar NRAS2 genomic profile in 14 of 18 cases (all WT). Of interest, we noted a relatively high prevalence of KRAS mutations (five of 18, 28%). The frequency of KRAS mutations in the melanocytic aggregate (five of 18, 28%) was second to BRAF V600E, while in melanoma, the frequency was also second to BRAF V600E but equalled that of NRAS2 (1 of 18, 6%). No NRAS1 mutations were observed. BRAF and RAS mutations appeared to be mutually exclusive with only three of 18 cases (17%) demonstrating a mutation in both genes (melanocytic aggregate only).

Conclusions: Our findings hint towards the interpretation of banal melanocytic aggregates serving as precursor lesions.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Codon / genetics
  • DNA Mutational Analysis
  • Early Detection of Cancer
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Genes, ras / genetics*
  • Humans
  • Insulin-Like Growth Factor Binding Proteins / genetics
  • Insulin-Like Growth Factor Binding Proteins / metabolism
  • Male
  • Melanoma / genetics*
  • Melanoma / pathology
  • Middle Aged
  • Mutation / genetics*
  • Nevus, Pigmented / genetics
  • Nevus, Pigmented / pathology
  • Proto-Oncogene Proteins B-raf / genetics*
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology


  • Codon
  • Insulin-Like Growth Factor Binding Proteins
  • insulin-like growth factor binding protein-related protein 1
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf