title: Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3.
abstract: Gene expression profiles and chromosome 3 copy number divide uveal melanomas into two distinct classes correlating with prognosis. Using exome sequencing, we identified recurrent somatic mutations in EIF1AX and SF3B1, specifically occurring in uveal melanomas with disomy 3, which rarely metastasize. Targeted resequencing showed that 24 of 31 tumors with disomy 3 (77%) had mutations in either EIF1AX (15; 48%) or SF3B1 (9; 29%). Mutations were infrequent (2/35; 5.7%) in uveal melanomas with monosomy 3, which are associated with poor prognosis. Resequencing of 13 uveal melanomas with partial monosomy 3 identified 8 tumors with a mutation in either SF3B1 (7; 54%) or EIF1AX (1; 8%). All EIF1AX mutations caused in-frame changes affecting the N terminus of the protein, whereas 17 of 19 SF3B1 mutations encoded an alteration of Arg625. Resequencing of ten uveal melanomas with disomy 3 that developed metastases identified SF3B1 mutations in three tumors, none of which targeted Arg625.
authors.affiliation: Genome Informatics, Faculty of Medicine, Institute of Human Genetics, University of Duisburg-Essen, Essen, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Martin
authors.forename: Lars
authors.initials: L
authors.lastname: Maßhöfer
authors.forename: Petra
authors.initials: P
authors.lastname: Temming
authors.forename: Sven
authors.initials: S
authors.lastname: Rahmann
authors.forename: Claudia
authors.initials: C
authors.lastname: Metz
authors.forename: Norbert
authors.initials: N
authors.lastname: Bornfeld
authors.forename: Johannes
authors.initials: J
authors.lastname: van de Nes
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein-Hitpass
authors.forename: Alan G
authors.initials: AG
authors.lastname: Hinnebusch
authors.forename: Bernhard
authors.initials: B
authors.lastname: Horsthemke
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Lohmann
authors.forename: Michael
authors.initials: M
authors.lastname: Zeschnigk
mesh_terms: D000595:Amino Acid Sequence; D000782:Aneuploidy; D002893:Chromosomes, Human, Pair 3; D056915:DNA Copy Number Variations; D015977:Eukaryotic Initiation Factor-1 / Q000737:chemistry / Q000235:genetics*; D059472:Exome; D005260:Female; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009006:Monosomy / Q000235:genetics; D009154:Mutation; D009362:Neoplasm Metastasis; D010750:Phosphoproteins / Q000235:genetics*; D011379:Prognosis; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics*; D016415:Sequence Alignment; D014604:Uveal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000098943:Uveal Melanoma
chemical_list: D015977:Eukaryotic Initiation Factor-1; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; C026022:eukaryotic peptide initiation factor-1A