SF3B1 mutations are associated with alternative splicing in uveal melanoma

Cancer Discov. 2013 Oct;3(10):1122-1129. doi: 10.1158/2159-8290.CD-13-0330. Epub 2013 Jul 16.


Uveal melanoma, the most common eye malignancy, causes severe visual morbidity and is fatal in approximately 50% of patients. Primary uveal melanoma can be cured by surgery or radiotherapy, but the metastatic disease is treatment refractory. To understand comprehensively uveal melanoma genetics, we conducted single-nucleotide polymorphism arrays and whole-genome sequencing on 12 primary uveal melanomas. We observed only approximately 2,000 predicted somatic single-nucleotide variants per tumor and low levels of aneuploidy. We did not observe an ultraviolet radiation DNA damage signature, but identified SF3B1 mutations in three samples and a further 15 mutations in an extension cohort of 105 samples. SF3B1 mutations were associated with good prognosis and were rarely coincident with BAP1 mutations. SF3B1 encodes a component of the spliceosome, and RNA sequencing revealed that SF3B1 mutations were associated with differential alternative splicing of protein coding genes, including ABCC5 and UQCC, and of the long noncoding RNA CRNDE.

Significance: Our data show that despite its dismal prognosis, uveal melanoma is a relatively simple genetic disease characterized by recurrent chromosomal losses and gains and a low mutational burden. We show that SF3B1 is recurrently mutated in uveal melanoma, and the mutations are associated with aberrant alternative splicing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Genetic Variation
  • Humans
  • Melanoma / diagnosis
  • Melanoma / genetics*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism
  • Mutation
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism*
  • Polymorphism, Single Nucleotide
  • Prognosis
  • RNA Splicing Factors
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism
  • Ribonucleoprotein, U2 Small Nuclear / genetics*
  • Ribonucleoprotein, U2 Small Nuclear / metabolism*
  • Sequence Analysis, DNA
  • Spliceosomes / physiology
  • Tumor Suppressor Proteins / genetics
  • Ubiquitin Thiolesterase / genetics
  • Uveal Neoplasms / diagnosis
  • Uveal Neoplasms / genetics*


  • ABCC5 protein, human
  • BAP1 protein, human
  • CRNDE RNA, human
  • Membrane Proteins
  • Multidrug Resistance-Associated Proteins
  • Phosphoproteins
  • RNA Splicing Factors
  • RNA, Long Noncoding
  • Ribonucleoprotein, U2 Small Nuclear
  • SF3B1 protein, human
  • Tumor Suppressor Proteins
  • UQCC protein, human
  • Ubiquitin Thiolesterase

Supplementary concepts

  • Uveal melanoma