To the Editor
Melanoma is a heterogeneous cancer consisting of different subsets. Uveal melanoma is a distinct subtype with clinical, biologic, and genetic differences from cutaneous melanoma.1 It arises from melanocytes of the iris, ciliary body or the choroid, the latter being the most common location. Predisposing factors include uveal nevus and nevus of Ota. It is an aggressive tumor with approximately half of patients resulting in metastasis. The site of metastasis is the liver due to hematogenous spread. In contrast to cutaneous melanoma, lymphatic dissemination does not occur due to an absence of lymphatic drainage of the ocular interior. The cytogenetic abnormalities (chromosomal aberrations) of the tumor and gene expression profiles are different from cutaneous melanoma.1 Monosomy 3 and gain of chromosome 8q within the tumor associate with a metastatic phenotype whereas gain of chromosome 6p occurs in tumors with low metastatic risk. Similarly, gene expression signatures accurately distinguish tumors at low metastatic and high metastatic risk.1 Somatic genetic alterations observed in uveal melanoma show differences compared to cutaneous melanoma. Gain-of-function mutations in BRAF (40-50%) or NRAS (15-25%) are common among cutaneous melanomas of the trunk and extremities.2 Increase gene dosage or mutations of KIT (39%) are observed among acral melanomas.3 BRAF, NRAS, KIT mutations are extremely rare in uveal melanoma.4 These genetic alterations lead to activation of the RAS-ERK pathway that is critical for proliferation, survival, migration, and differentiation signals and is virtually activated in the majority of melanomas.
Recently, gain-of-function mutations in the GNAQ gene that leads to RAS-ERK activation have been reported in uveal melanoma (83%) as well as in other melanocytic tumors (summarized in Table 1).5-8 The mutational profile of GNAQ has not been validated in large cohorts of cutaneous melanoma. Here, we report sequencing of the hotspot regions of the GNAQ gene (exon 5) as described previously5 in a cohort of cutaneous melanomas (n=122) consisting of melanomas of the trunk and extremities (n=83), acral sites (n=25), and unknown sites (n=14). Due to sequence homology to GNAQ, mutations in GNA11 gene were also tested. BRAF mutations were found in 53 (44%) and NRAS in 23 cases (19%), however no mutations in GNAQ or GNA11 were identified. This study validates recent findings that somatic mutations in GNAQ are rare, if any, among melanomas that arise from epidermal melanocytes of the trunk, extremities and acral sites.
Table 1.
Frequency of GNAQ Mutations in Benign and Malignant Neoplasms
| Neoplasm type | GNAQ mutations | Citation |
|---|---|---|
| Uveal melanoma | 46-49% | Onken et al, Van Raamsdonk et al |
| Mucosal melanoma | 0% | Van Raamsdonk et al, Present study |
| Cutaneous melanoma (acral sites) | 0% | Van Raamsdonk et al, Present study |
| Cutaneous melanoma (non-acral sites with chronic sun-induced damage) | 0-4% | Van Raamsdonk et al, Present study |
| Blue nevus | 46-83% | Lamba et al, Van Raamsdonk et al |
| Malignant blue nevus | 50% | Van Raamsdonk et al |
| Nevus of Ota | 6-46% | Lamba et al, Van Raamsdonk et al |
| Congenital nevus | 0% | Van Raamsdonk et al |
| Deep penetrating nevus | 0% | Van Raamsdonk et al |
| Spitz nevus | 0% | Van Raamsdonk et al |
| Primary melanocytic neoplasms of the central nervous system | 37% | Kusters-Vandevelde et al |
| Other neoplasms (carcinoma of the breast, colon, bladder, lung, ovarian, pancreas, thyroid; gastrointestinal stromal tumor; glioma; acute myelogenous leukemia) | 0% | Lamba et al |
ND, not determined
Benign melanocytic proliferations have also been associated with somatic mutations of the oncogenes associated with melanoma suggesting that these events occur early during development of melanocytic tumors. Large number of nevi is a risk factor for cutaneous melanoma; BRAF mutations are common in these nevi.2 Giant congenital melanocytic nevus is a risk factor for cutanenous melanoma; NRAS mutations are common in this nevus subset.9 GNAQ mutations are found in blue nevus and nevus of Ota. Of interest, nevus of Ota is a known risk for uveal melanoma.1
In conclusion, mutations in GNAQ are unique to uveal melanoma subtype and are rare, if any, in cutaneous melanoma. A full characterization of the melanocyte development pathways as well as identification of genetic events underlying benign and malignant melanocytic tumors, functional characterization of these genetic events and clinical correlative studies will eventually lead to comprehensive understanding of melanocytic tumors.
Acknowledgments
Funding sources: Funded in part by a grant from the National Institutes of Health/National Cancer Institute R01 CA138678 (to JTC).
Footnotes
Conflict of interest: None declared.
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References
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