title: SF3B1 mutations are associated with alternative splicing in uveal melanoma.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Cancer Research UK Manchester Institute, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Furney
authors.affiliation: The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Malin
authors.initials: M
authors.lastname: Pedersen
authors.affiliation: Institut Curie, Paris, 75248 France.|Platform of Molecular Biology facilities, Translational Research Department, Institut Curie, Paris, 75248 France.
authors.forename: David
authors.initials: D
authors.lastname: Gentien
authors.affiliation: Institut Curie, Paris, 75248 France.|INSERM U830, Paris, 75248 France.
authors.forename: Amaury G
authors.initials: AG
authors.lastname: Dumont
authors.affiliation: Institut Curie, Paris, 75248 France.|Platform of Molecular Biology facilities, Translational Research Department, Institut Curie, Paris, 75248 France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Rapinat
authors.affiliation: Institut Curie, Paris, 75248 France.|Department of Ophthalmological Surgery, Institut Curie, Paris, 75248 France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Desjardins
authors.affiliation: The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Samra
authors.initials: S
authors.lastname: Turajlic
authors.affiliation: Institut Curie, Paris, 75248 France.|Department of Medical Oncology, Institut Curie, Paris, 75248 France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Piperno-Neumann
authors.affiliation: GenoSplice, Hopital Saint-Louis, Paris, 75010 France.
authors.forename: Pierre
authors.initials: P
authors.lastname: de la Grange
authors.affiliation: Institut Curie, Paris, 75248 France.|INSERM U830, Paris, 75248 France.
authors.forename: Sergio
authors.initials: S
authors.lastname: Roman-Roman
authors.affiliation: Institut Curie, Paris, 75248 France.|Platform of Molecular Biology facilities, Translational Research Department, Institut Curie, Paris, 75248 France.
authors.forename: Marc-Henri
authors.initials: MH
authors.lastname: Stern
authors.affiliation: The Cancer Research UK Manchester Institute, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
mesh_terms: D017398:Alternative Splicing; D014644:Genetic Variation; D006801:Humans; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D000072260:RNA Splicing Factors; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics* / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D017381:Spliceosomes / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics; D014604:Uveal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D000098943:Uveal Melanoma
chemical_list: D008565:Membrane Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D062085:RNA, Long Noncoding; D017413:Ribonucleoprotein, U2 Small Nuclear; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase; C120809:ABCC5 protein, human; C400134:BAP1 protein, human; C586983:CRNDE RNA, human; C112491:SF3B1 protein, human; C582875:UQCC1 protein, human