A recent study indicates that somatic mutations in
codon 209 of GNAQ, a gene encoding the signaling
protein G-protein α subunit q, may be present in up to 80% of
blue nevi. Given that mutations in GNAQ represent dominant dark skin (Dsk) mutations caused by increased dermal
melanin, the primary aim of this study was to ascertain whether amelanotic/hypomelanotic
blue nevi exhibited somatic mutations in GNAQ like their melanotic counterpart. Genomic
DNA was isolated for genotyping per protocol using techniques including
laser capture microdissection to isolate
nevus cells from amelanotic/hypomelanotic
blue nevi (n = 8). The positive control group comprised regular
blue nevi (n = 10, all melanotic) and
cellular blue nevi (n = 9, all melanotic), whereas the negative control group comprised other dermal-based nevomelanocytic proliferations such as intradermal
melanocytic nevi (n = 9, 7 of which were amelanotic) and metastatic
melanoma (n = 9, 5 of which were amelanotic).
DNA sequencing analysis was performed on GNAQ spanning
codon 209, BRAFV600E, NRAS1, NRAS2, and KRAS genes. Mutations in GNAQ were noted in 12.5% (1/8) of amelanotic/hypomelanotic
blue nevi. In the control group 40% (4/10) of
blue nevi and 44% (4/9) of
cellular blue nevi demonstrated the GNAQ mutation, with no cases of metastatic
melanoma or intradermal
melanocytic nevi exhibiting the mutation. All GNAQ mutations were A/T point mutations, and statistically significant differences were not noted among the amelanotic/hypomelanotic
blue nevi,
blue nevi, and
cellular blue nevi subgroups. Although additional mutations were not noted in cases of amelanotic/hypomelanotic
blue nevi, one
blue nevus exhibited a mutation in KRAS alone; one
cellular blue nevus, a concurrent NRAS2 mutation; one
cellular blue nevus, a concurrent KRAS mutation; and a third
cellular blue nevus, a mutation in KRAS alone. The presence of GNAQ mutations in the amelanotic/hypomelanotic
blue nevus indicates that mechanisms underlying pigment homeostasis in this variant appear to be similar to those of its melanotic counterparts, although it is not clear why activation of the q class of the
G-protein α subunit should cause an abundance of dermal pigment in one variant and not in another. Given that dermal melanocytes are present since birth, one possible explanation is that their
melanin-synthesizing pathway is usually in a dormant state. Activation of this pathway is a consequence of multiple triggers-one of which is a mutation in the GNAQ gene, whereas the other is yet to be identified.