Uveal Melanoma: Molecular Pathology

  • Sarah E. CouplandEmail author
  • Helen Kalirai
  • Sophie Thornton
  • Bertil E. Damato


Research into the molecular genetics of uveal melanomas (UM) has identified several predictors of metastatic disease as well as signaling pathways and molecules that can be targeted using systemic therapies. Most UM have GNAQ/11 initiating mutations, which activate the MAPK pathway, with dysregulation of the PI3K/AKT and other signaling pathways. Some patients develop UM because they have inherited the BAP-1 tumor predisposition syndrome, which also causes malignant mesothelioma and renal cell carcinoma. Metastasis is associated with many genetic aberrations, particularly chromosome 3 deletion, chromosome 8q gain, and somatic BAP1 mutation, whereas SF3B1 mutation predicts late metastasis, while chromosome 6p gain, and EIF1AX and CNKSR3 mutations are associated with a good prognosis. Recent data from The Cancer Genome Atlas (TCGA) indicate four prognostic groups of UM, categorized according to chromosome copy number variations, mutations and DNA methylation profiles. Other abnormalities include PTEN inactivation, inhibition of the retinoblastoma and p53 pathways, cyclin D1 overexpression, and CDKN2a promoter hypermethylation. Several potential MAPK/MEK, PI3K/AKT targets for UM therapy have been identified, using mTOR inhibitors, tyrosine kinase inhibitors, c-Met pathway inhibitors, CXCR4 small molecule inhibitors, histone deacetylase inhibitors, and others.




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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Sarah E. Coupland
    • 1
    Email author
  • Helen Kalirai
    • 1
  • Sophie Thornton
    • 1
  • Bertil E. Damato
    • 2
  1. 1.Department of Molecular and Clinical Cancer Medicine, Institute of Translational MedicineUniversity of LiverpoolLiverpool, MerseysideUK
  2. 2.Nuffield Department of Clinical NeurosciencesUniversity of Oxford, John Radcliffe HospitalOxfordUK

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