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 article

18 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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