T h e new england journal o f medicine

e di t or i a l

Taking the Guesswork Out of Uveal Melanoma Meenhard Herlyn, D.V.M., D.Sc., and Katherine L. Nathanson, M.D.

Therapy for melanoma is making remarkable tors and their downstream effectors — in particu- progress. Only 8 years after the initial discovery lar, alpha subunits of the heterotrimeric of mutations in the BRAF oncogene, a new small- binding to guanosine triphosphate (GTP) — are molecule inhibitor specific for mutant BRAF, emerging as an important source of susceptibil- PLX4032 (also known as RG7204), induced tumor ity to cancer in humans. Heterotrimeric GTP- shrinkage in more than 80% of patients with cu- binding proteins are made up of three subunits: taneous melanoma containing BRAF mutations alpha, beta, and gamma. When inactive, the al- and extended progression-free survival by an av- pha subunit binds guanosine diphosphate (GDP). erage of 7 months.1,2 Although BRAF-targeted When the alpha subunit is stimulated by an acti- therapy is not curative, it is possible that its com- vated G-–coupled receptor, it too becomes bination with immunotherapy to potentiate anti- activated, binding to GTP (thereby forcing its dis- tumor T-cell responses may lead to durable re- sociation from the beta and gamma subunits, sponses.3 The mutant BRAF amino acid that is which remain attached to one another) and set- targeted by PLX4032 is present in 50% of cutane- ting off a chain of signaling events. Within the ous melanomas but is absent from certain other binding site of the alpha subunit, GTP binds to a subtypes of the disease, such as uveal melano- specific glutamine or arginine at amino acid po- ma, which represents 5% of all melanomas. sition 209 — which in its mutated form results in Uveal melanoma, the most common intraocu- constitutive G-protein activation. Mutations have lar cancer, arises from melanocytes within the been reported in encoding other hetero- choroidal plexus of the eye and metastasizes al- trimeric G-protein alpha subunits in a variety of most exclusively to the liver. Building on their cancers, and these mutations also affect arginine earlier work,4 Van Raamsdonk et al.5 report in this or glutamine residues that bind to GTP or GDP. issue of the Journal that more than 80% of uveal GNAS (a homologue of GNAQ and GNA11) is am- melanomas carry mutations in either GNA11 or plified in 12% of ovarian carcinomas, in 20% of GNAQ. These genes encode members of the q class breast cancers that are negative for human epi- of G-protein alpha subunits, which are involved in dermal growth factor receptor 2 (HER2), and in mediating signals between G-protein–coupled re- 13% of hormone-receptor–positive breast carcino- ceptors and downstream effectors, such as pro- mas.6 Furthermore, the expression of the G-pro- tein kinases A and C. The proteins encoded by tein–coupled receptor encoded by Grm1 induces

GNAQ and GNA11 — Gαq and Gα11, respectively melanomas in transgenic mice with 100% pen- — have 90% with each oth- etrance.7 er but appear to have differing functional roles. In both studies, Van Raamsdonk et al.4,5 re- Both proteins have oncogenic activities and can port the presence of GNAQ and GNA11 mutations transform melanocytes, albeit only those that have in blue nevi (benign intradermal melanocytic pro- been immortalized, suggesting that mutation of liferations affecting the conjunctiva and perior- either is necessary but not sufficient for ma- bital skin) in addition to uveal melanoma. Patients lignant transformation. with blue nevi are at risk for uveal melanoma. Mutations affecting G-protein–coupled recep- GNAQ or GNA11 mutations have not been identi-

2256 n engl j med 363;23 nejm.org december 2, 2010 The New England Journal of Medicine Downloaded from nejm.org at UNIV OF PENN LIBRARY on March 1, 2011. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved. editorial fied in cutaneous melanomas, but GNAQ muta- mation, aberrations in other pathways are prob- tions have been detected in melanocytic tumors ably critical to the genesis of uveal melanoma. of the central nervous system, suggesting that a The identification of these pathways would be a stem cell capable of giving rise to both neuronal useful next step. cells and melanocytes is the target for transfor- Disclosure forms provided by the authors are available with mation. Indeed, such a stem cell has been iden- the full text of this article at NEJM.org. tified in the human dermis.8 From the Wistar Institute (M.H.); and the Department of Medicine Epidemiologic studies point to a causative role and the Abramson Cancer Center, University of Pennsylvania (K.L.N.) — both in Philadelphia. for ultraviolet irradiation in uveal and cutaneous melanoma, but the types of mutations in GNAQ, This article (10.1056/NEJMe1010681) was published on Novem- ber 17, 2010, at NEJM.org. GNA11, and BRAF are not typically induced by me- dium-wave ultraviolet B light (315 to 280 nm). It 1. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010; is less clear what effect ultraviolet A light (320 to 363:809-19. 400 nm) has on DNA, since such long-wave light 2. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF in- can induce reactive oxygen species, which are hibitor needs broad target blockade in BRAF-mutant melanoma. Nature 2010;467:596-9. greatly enhanced by melanin. Potentially, oxida- 3. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival tive stress and oxidative damage induced by ul- with ipilimumab in patients with metastatic melanoma. N Engl traviolet A light are the two major contributors J Med 2010;363:711-23. [Erratum, N Engl J Med 2010;363:1290.] 4. Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent to the genesis of melanoma, since melanocytes somatic mutations of GNAQ in uveal melanoma and blue naevi. are highly sensitive to oxidative damage, with a Nature 2009;457:599-602. repair capacity lower than that of skin fibroblasts.9 5. Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Muta- tions in GNA11 in uveal melanoma. N Engl J Med 2010. DOI: The downstream effectors of Gαq and Gα11 re- 10.1056/NEJMoa1000584. main to be elucidated and are potential targets 6. Kan Z, Jaiswal BS, Stinson J, et al. Diverse somatic mutation for therapy. In their previous study, Van Raams- patterns and pathway alterations in human cancers. Nature 4 2010;466:869-73. donk et al. observed activation of the mitogen- 7. Pollock PM, Cohen-Solal K, Sood R, et al. Melanoma mouse activated pathway consequent to model implicates metabotropic glutamate signaling in melano- cytic neoplasia. Nat Genet 2003;34:108-12. increased production of Gαq and Gα11 through 8. Li L, Fukunaga-Kalabis M, Yu H, et al. Human dermal stem mutation, leading them to propose clinical trials cells differentiate into functional epidermal melanocytes. J Cell with MEK inhibitors to treat uveal melanoma. Sci 2010;123:853-60. A phase 2 clinical trial is under way. 9. Wang HT, Choi B, Tang MS. Melanocytes are deficient in repair of oxidative DNA damage and UV-induced photoproducts. Because mutation of GNA11 or GNAQ is not suf- Proc Natl Acad Sci U S A 2010;107:12180-5. ficient on its own to induce malignant transfor- Copyright © 2010 Massachusetts Medical Society.

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n engl j med 363;23 nejm.org december 2, 2010 2257 The New England Journal of Medicine Downloaded from nejm.org at UNIV OF PENN LIBRARY on March 1, 2011. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.