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Uveal Melanomas with SF3B1 Mutations

A Distinct Subclass Associated with Late-Onset Metastases
  • Author Footnotes
    ∗ Both Serdar Yavuzyigitoglu, MD, and Anna E. Koopmans, MD, PhD, contributed equally as first authors.∗Rotterdam Ocular Melanoma Study Group (ROMS) is a collaborative research group with members from the Rotterdam Eye Hospital, Departments of Ophthalmology, Pathology and Clinical Genetics, of the Erasmus MC, Rotterdam, the Netherlands (http://www.erasmusmc.nl/oogheelkunde/research/ROMS/).
    Serdar Yavuzyigitoglu
    Footnotes
    ∗ Both Serdar Yavuzyigitoglu, MD, and Anna E. Koopmans, MD, PhD, contributed equally as first authors.
    ∗ ∗Rotterdam Ocular Melanoma Study Group (ROMS) is a collaborative research group with members from the Rotterdam Eye Hospital, Departments of Ophthalmology, Pathology and Clinical Genetics, of the Erasmus MC, Rotterdam, the Netherlands (http://www.erasmusmc.nl/oogheelkunde/research/ROMS/).
    Affiliations
    Department of Ophthalmology, Erasmus University Medical Centre, Rotterdam, The Netherlands

    Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands
    Search for articles by this author
  • Author Footnotes
    ∗ Both Serdar Yavuzyigitoglu, MD, and Anna E. Koopmans, MD, PhD, contributed equally as first authors.∗Rotterdam Ocular Melanoma Study Group (ROMS) is a collaborative research group with members from the Rotterdam Eye Hospital, Departments of Ophthalmology, Pathology and Clinical Genetics, of the Erasmus MC, Rotterdam, the Netherlands (http://www.erasmusmc.nl/oogheelkunde/research/ROMS/).
    Anna E. Koopmans
    Footnotes
    ∗ Both Serdar Yavuzyigitoglu, MD, and Anna E. Koopmans, MD, PhD, contributed equally as first authors.
    ∗ ∗Rotterdam Ocular Melanoma Study Group (ROMS) is a collaborative research group with members from the Rotterdam Eye Hospital, Departments of Ophthalmology, Pathology and Clinical Genetics, of the Erasmus MC, Rotterdam, the Netherlands (http://www.erasmusmc.nl/oogheelkunde/research/ROMS/).
    Affiliations
    Department of Ophthalmology, Erasmus University Medical Centre, Rotterdam, The Netherlands

    Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands
    Search for articles by this author
  • Robert M. Verdijk
    Affiliations
    Department of Pathology, Erasmus University Medical Centre, Rotterdam, The Netherlands
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  • Jolanda Vaarwater
    Affiliations
    Department of Ophthalmology, Erasmus University Medical Centre, Rotterdam, The Netherlands

    Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands
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  • Bert Eussen
    Affiliations
    Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands
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  • Alice van Bodegom
    Affiliations
    Department of Ophthalmology, Erasmus University Medical Centre, Rotterdam, The Netherlands

    Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands
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  • Dion Paridaens
    Affiliations
    The Rotterdam Eye Hospital, Rotterdam, The Netherlands
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  • Emine Kiliç
    Affiliations
    Department of Ophthalmology, Erasmus University Medical Centre, Rotterdam, The Netherlands
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  • Annelies de Klein
    Correspondence
    Correspondence: Annelies de Klein, PhD, Department of Clinical Genetics, Room Ee2471, Erasmus University Medical Centre, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
    Affiliations
    Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands
    Search for articles by this author
  • on behalf of theRotterdam Ocular Melanoma Study Group
  • Author Footnotes
    ∗ Both Serdar Yavuzyigitoglu, MD, and Anna E. Koopmans, MD, PhD, contributed equally as first authors.∗Rotterdam Ocular Melanoma Study Group (ROMS) is a collaborative research group with members from the Rotterdam Eye Hospital, Departments of Ophthalmology, Pathology and Clinical Genetics, of the Erasmus MC, Rotterdam, the Netherlands (http://www.erasmusmc.nl/oogheelkunde/research/ROMS/).
Published:February 25, 2016DOI:https://doi.org/10.1016/j.ophtha.2016.01.023

      Purpose

      To investigate the prevalence and prognostic value of SF3B1 and EIF1AX mutations in uveal melanoma (UM) patients.

      Design

      Case series.

      Participants

      Cohort of 151 patients diagnosed with and treated for UM.

      Methods

      SF3B1 and EIF1AX mutations in primary tumors were investigated using whole-exome sequencing (n = 25) and Sanger sequencing (n = 151). For the detection of BAP1 mutations, a previously reported cohort of 90 patients was extended using BAP1 sequencing or immunohistochemistry.

      Main Outcome Measures

      The status of SF3B1, EIF1AX, and BAP1 in tumors of patients were correlated to clinical, histopathologic, and genetic parameters. Survival analyses were performed for patients whose tumors had SF3B1, EIF1AX, and BAP1 mutations.

      Results

      Patients with tumors harboring EIF1AX mutations rarely demonstrated metastases (2 of 28 patients) and overall had a longer disease-free survival (DFS; 190.1 vs. 100.2 months; P < 0.001). Within the patient group with disomy 3, UM patients with an SF3B1 mutation had an increased metastatic risk compared with those without an SF3B1 mutation (DFS, 132.8 vs. 174.4 months; P = 0.008). Patients with such a mutation were more prone to demonstrate late metastases (median, 8.2 years; range, 23–145 months). Patients with UM and loss of BAP1 expression had a significantly decreased survival (DFS, 69.0 vs. 147.9 months; P < 0.001).

      Conclusions

      According to our data, patients with UM can be classified into 3 groups, of which EIF1AX-mutated tumors and tumors without BAP1, SF3B1, or EIF1AX mutations are associated with prolonged survival and low metastatic risk, SF3B1-mutated tumors are associated with late metastasis, and tumors with an aberrant BAP1 are associated with an early metastatic risk and rapid decline in patient DFS.

      Abbreviations and Acronyms:

      BAP1 (BRCA-associated protein 1), DFS (disease-free survival), EIF1AX (eukaryotic translation initiation factor 1A), GNAQ (Guanine nucleotide-binding protein G(q) subunit alpha), GNA11 (Guanine nucleotide-binding protein G(q) subunit alpha 11), HR (hazard ratio), SF3B1 (splicing factor 3 subunit B1), UM (uveal melanoma)
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