Somatic mutations in GNAQ in amelanotic/hypomelanotic blue nevi

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.