Oncogenic signaling in uveal melanoma

John Park, Russell J. Diefenbach, Anthony M. Joshua, Richard F. Kefford, Matteo S. Carlino, Helen Rizos*

*Corresponding author for this work

    Research output: Contribution to journalReview articlepeer-review

    36 Citations (Scopus)

    Abstract

    Uveal melanoma is the most common primary cancer of the eye, and despite rapidly emerging insights into the molecular profile of this disease, prognosis of patients with metastatic uveal melanoma remains poor with mortality rates unchanged in over 35 years. Early genetic events activate G protein-coupled receptor signaling in nearly all uveal tumors via mutually exclusive mutations in the GNAQ, GNA11, CYSLTR2, or PLCB4 genes. A multitude of signaling cascades downstream of G protein activation, including protein kinase C and mitogen-activated protein kinase activity, are action- able, and many ongoing clinical trials are targeting these pathways. Additional cytogenetic and genetic changes, however, including chromosome 3 monosomy, mutations in the BAP1 tumor suppressor gene, alterations in the splicing factors SRSF2/SF3B1, and mutations in the translation initiation factor EIF1AX, modulate signaling output in uveal tumors and modify the risk of metastases. Here, we review the complex interactions between genetic, molecular signaling, and prognostic pro- files in uveal melanoma; the clinical implications of these interactions; and the latest potential targets for rational therapy.
    Original languageEnglish
    Pages (from-to)661-672
    Number of pages12
    JournalPigment Cell and Melanoma Research
    Volume31
    Issue number6
    DOIs
    Publication statusPublished - Nov 2018

    Keywords

    • BAP1
    • G protein-coupled receptor
    • GNAQ/GNA11
    • mitogen-activated protein kinase
    • uveal melanoma

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