somatic mutations are rare in blue nevi,11,18
our data show that they are well represented in uveal melanoma. In our samples, 83.0% of uveal melanomas had a constitutively active mutation in either GNAQ
, suggesting that activation of the Gαq
pathway is the predominant route to the development of uveal melanoma. GNAQ
have overlapping functions in melanocytes,9
and both genes upregulate the MAP kinase pathway when constitutively active. Although Gαq
have amino acid sequences that are 90% homologous, there appear to be differences in their role in melanocytic neoplasia.
Several lines of evidence suggest that GNA11
mutations may have a more potent effect on melanocytes than do mutations in GNAQ
. First, GNA11
mutations were rare in blue nevi, which are benign neoplasms.26
Conversely, there were significantly more GNA11
Q209 mutations than GNAQ
Q209 mutations in uveal melanoma metastases. Furthermore, GNA11
mutations were more common in locally advanced primary tumors and in primary tumors originating from the ciliochoroidal region, a prognostically adverse feature.29
Finally, the mouse Gna11
Dsk7 mutation is more tumorigenic than the Gnaq
Dsk1 mutation, since it is better able to stimulate melanocyte growth that is impaired by heterozygous mutations in Kit
, and Ednrb
(encoding endothelin receptor type B).9
However, since the mutations found in mice occur at different residues in Gna11
(I63V and V179 M, respectively),9
we cannot dismiss the possibility that the difference is a functional consequence of the mutations themselves, rather than a difference in function between Gna11
Although the survival of patients did not differ significantly among those with GNAQ mutations and those with GNA11 mutations in our study, the number of patients who were available for our analysis may have been too small to detect such a difference. In addition, we used enucleated specimens, which could have biased the analysis; tissue for mutation analysis is not routinely available from nonenucleated samples. The samples that we analyzed were typically from large tumors, which may have obscured any association between mutations in GNAQ or GNA11 and prognosis.
The level of activation of Gαq
R183 mutants is considerably lower than that of Gαq
Q209 mutants in vitro, which raises the possibility that R183-mutated oncoproteins may be less potent.27
Our finding of an increased latency and reduced penetrance in the tumorigenicity assay is consistent with this notion. Of possible clinical relevance is the finding that Gαq
R183 but not Gαq
Q209 can be inhibited with YM-254890, a naturally occurring toxin from chromobacteria.30
In a recent study of GNAQ
in 922 human neoplasms with various histopathological features, the only mutations that were found were in GNAQ
in blue nevi.18
Samples of uveal melanoma were not included in the study. Although these results are not exhaustive, together with our data, they suggest that GNAQ
mutations are enriched in the melanocytic lineage. Another study showed that GNAQ
mutations were present in 37% of melanocytic neoplasms of the central nervous system,17
making it likely that GNA11
mutations will also be found in this category of melanocytic tumors.
The peculiar association among mutations in melanocytic neoplasms of the dermis, uvea, and central nervous system may indicate different cells of origin. A developmental pathway has been described,31
in which a subgroup of melanocytes derives from a precursor shared with Schwann cells. It is possible that Gαq
signaling has a critical role in the production of melanocytes through this developmental mechanism. If so, the timing of the occurrence of mutations may determine the localization and extent of the neoplasm. Lesions that are confined to the central nervous system would arise from Gαq
mutations in precursors before the onset of migration, and segmental lesions, such as the nevus of Ota, would result from mutations in a precursor early during migration, in contrast to mutations arising later along the migratory pathway, which would result in solitary lesions involving the skin or choroid.
Epidemiologic studies have shown conflicting roles for recreational and occupational exposure to ultraviolet radiation in patients with uveal melanoma.32,33
Fair complexion and light irides are generally considered risk factors for uveal melanoma.34,35
Some studies have shown that uveal melanomas most frequently arise in the macula region, which has the highest level of exposure to ultraviolet radiation.36
Our finding of cytosine-to-thymine transitions in uveal melanomas could suggest a role for ultraviolet radiation.
In summary, our findings suggest that a large majority of uveal melanomas and blue nevi carry mutations in either GNAQ or GNA11.