title: Chromosome 3 status combined with BAP1 and EIF1AX mutation profiles are associated with metastasis in uveal melanoma.
abstract: OBJECTIVE
  Somatic mutations in GNAQ, GNA11, SF3B1, EIF1AX, and BAP1 have been identified in uveal melanoma (UM). The aim of this study was to determine whether mutations in these genes in primary tumors were associated with metastases in individuals diagnosed with UM.
  
  
  METHODS
  A total of 63 UM cases who developed a metastasis within 48 months of primary treatment and 53 UM controls who were metastasis-free over a similar time period were selected for the study. Primary UM cases were screened for mutations in GNAQ, GNA11, SF3B1, EIF1AX, and BAP1. The association of these mutations with tumor characteristics, chromosome 3 copy number, and metastatic status was analyzed by logistic regression to estimate the odds of developing metastasis within 48 months.
  
  
  RESULTS
  As expected, tumor diameter, thickness, cilio-choroidal location, and chromosome 3 monosomy were all significantly (P < 0.02) associated with the presence of metastasis. In univariate analysis, GNA11 (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.1-5.5) and BAP1 (OR 6.3, 95% CI 2.7-14.4) mutations were positively associated and EIF1AX mutation (OR 0.13, 95% CI 0.034-0.47) was inversely associated with metastatic status at 48 months after UM treatment. After adjustment for covariates, a chromosome 3 monosomy/BAP1-mutation/EIF1AX-wild-type (WT) mutation profile was strongly associated (OR 37.5, 95% CI 4.3-414) with the presence of metastasis compared with a chromosome 3 disomy/BAP1-WT/EIF1AX mutation profile.
  
  
  CONCLUSIONS
  The results suggest that knowledge of mutations in BAP1 and EIF1AX can enhance prognostication of UM beyond that determined by chromosome 3 and tumor characteristics. Tumors with chromosome 3 disomy/BAP1-WT/EIF1AX-WT have a 10-fold increased risk of metastasis at 48 months compared with disomy-3/BAP1-WT/EIF1AX mutant tumors.
authors: Genetic Diagnostic Laboratory, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.
authors: Kathryn G
authors: KG
authors: Ewens
authors: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States.
authors: Peter A
authors: PA
authors: Kanetsky
authors: Genetic Diagnostic Laboratory, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.
authors: Jennifer
authors: J
authors: Richards-Yutz
authors: Genetic Diagnostic Laboratory, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.
authors: Juliana
authors: J
authors: Purrazzella
authors: The Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, United States.
authors: Carol L
authors: CL
authors: Shields
authors: Penn Genomic Analysis Core, DNA Sequencing Facility, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.
authors: Tapan
authors: T
authors: Ganguly
authors: Genetic Diagnostic Laboratory, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States.
authors: Arupa
authors: A
authors: Ganguly
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D004252:DNA Mutational Analysis; D015977:Eukaryotic Initiation Factor-1 / Q000235:genetics*; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006801:Humans; D016015:Logistic Models; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000556:secondary*; D008875:Middle Aged; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*; D014604:Uveal Neoplasms / Q000235:genetics* / Q000556:secondary*; D055815:Young Adult; D000098943:Uveal Melanoma
chemical_list: C400134:BAP1 protein, human; D015977:Eukaryotic Initiation Factor-1; C554062:GNA11 protein, human; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; D025521:Tumor Suppressor Proteins; C026022:eukaryotic peptide initiation factor-1A; D043222:Ubiquitin Thiolesterase; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
keywords: BAP1; EIF1AX; GNA11; GNAQ; SF3B1; chromosome 3; somatic mutation; uveal melanoma