Driver Mutations in Uveal Melanoma: Associations With Gene Expression Profile and Patient Outcomes.
Frequent mutations have been described in the following 5 genes in uveal melanoma (UM): BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. Understanding the prognostic significance of these mutations could facilitate their use in precision medicine.



To determine the associations between driver mutations, gene expression profile (GEP) classification, clinicopathologic features, and patient outcomes in UM.



Retrospective study of patients with UM treated by enucleation by a single ocular oncologist between November 1, 1998, and July 31, 2014.



Clinicopathologic features, patient outcomes, GEP classification (class 1 or class 2), and mutation status were recorded.



The study cohort comprised 81 participants. Their mean age was 61.5 years, and 37% (30 of 81) were female. The GEP classification was class 1 in 35 of 81 (43%), class 2 in 42 of 81 (52%), and unknown in 4 of 81 (5%). BAP1 mutations were identified in 29 of 64 (45%), GNAQ mutations in 36 of 81 (44%), GNA11 mutations in 36 of 81 (44%), SF3B1 mutations in 19 of 81 (24%), and EIF1AX mutations in 14 of 81 (17%). Sixteen of the mutations in BAP1 and 6 of the mutations in EIF1AX were previously unreported in UM. GNAQ and GNA11 mutations were mutually exclusive. BAP1, SF3B1, and EIF1AX mutations were almost mutually exclusive with each other. Using multiple regression analysis, BAP1 mutations were associated with class 2 GEP and older patient. EIF1AX mutations were associated with class 1 GEP and the absence of ciliary body involvement. SF3B1 mutations were associated with younger patient age. GNAQ mutations were associated with the absence of ciliary body involvement and greater largest basal diameter. GNA11 mutations were not associated with any of the analyzed features. Using Cox proportional hazards modeling, class 2 GEP was the prognostic factor most strongly associated with metastasis (relative risk, 9.4; 95% CI, 3.1-28.5) and melanoma-specific mortality (relative risk, 15.7; 95% CI, 3.6-69.1) (P < .001 for both). After excluding GEP class, the presence of BAP1 mutations was the factor most strongly associated with metastasis (relative risk, 10.6; 95% CI, 3.4-33.5) and melanoma-specific mortality (relative risk, 9.0; 95% CI, 2.8-29.2) (P < .001 for both).



BAP1, SF3B1, and EIF1AX mutations occur during UM tumor progression in an almost mutually exclusive manner and are associated with different levels of metastatic risk. These mutations may have value as prognostic markers in UM.
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida3Interdisciplinary Stem Cell Institute, University of Miami Mill.
Christina L
CL
Decatur
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida3Interdisciplinary Stem Cell Institute, University of Miami Mill.
Erin
E
Ong
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida3Interdisciplinary Stem Cell Institute, University of Miami Mill.
Nisha
N
Garg
National Heart and Lung Institute, Imperial College of Science and Technology, London, England.
Hima
H
Anbunathan
National Heart and Lung Institute, Imperial College of Science and Technology, London, England.
Anne M
AM
Bowcock
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida3Interdisciplinary Stem Cell Institute, University of Miami Mill.
Matthew G
MG
Field
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida3Interdisciplinary Stem Cell Institute, University of Miami Mill.
J William
JW
Harbour
D004252:DNA Mutational Analysis; D015977:Eukaryotic Initiation Factor-1 / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D000072260:RNA Splicing Factors / Q000235:genetics*; D012189:Retrospective Studies; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*; D014604:Uveal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D000098943:Uveal Melanoma
C400134:BAP1 protein, human; D015977:Eukaryotic Initiation Factor-1; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; C112491:SF3B1 protein, human; D025521:Tumor Suppressor Proteins; C026022:eukaryotic peptide initiation factor-1A; D043222:Ubiquitin Thiolesterase