Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Cancer Cell. 2017 Aug 14;32(2):204-220.e15. doi: 10.1016/j.ccell.2017.07.003.


Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.

Keywords: EIF1AX; GNA11; GNAQ; SF3B1; SRSF2; TCGA; molecular subtypes; monosomy 3; noncoding RNA; uveal melanoma.

MeSH terms

  • Biomarkers, Tumor / genetics*
  • DNA Copy Number Variations
  • DNA Methylation*
  • Eukaryotic Initiation Factor-1 / genetics
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Melanoma / classification
  • Melanoma / genetics*
  • Monosomy
  • Mutation*
  • Phosphoproteins / genetics
  • Prognosis
  • RNA Splicing Factors / genetics
  • Serine-Arginine Splicing Factors / genetics
  • Tumor Suppressor Proteins / genetics
  • Ubiquitin Thiolesterase / genetics
  • Uveal Neoplasms / classification
  • Uveal Neoplasms / genetics*


  • BAP1 protein, human
  • Biomarkers, Tumor
  • Eukaryotic Initiation Factor-1
  • Phosphoproteins
  • RNA Splicing Factors
  • SF3B1 protein, human
  • SRSF3 protein, human
  • Tumor Suppressor Proteins
  • eukaryotic peptide initiation factor-1A
  • Serine-Arginine Splicing Factors
  • Ubiquitin Thiolesterase

Supplementary concepts

  • Uveal melanoma