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Original Investigation |

Driver Mutations in Uveal Melanoma Associations With Gene Expression Profile and Patient Outcomes

Christina L. Decatur, BS1,2,3; Erin Ong, BS, BA1,2,3; Nisha Garg, BS1,2,3; Hima Anbunathan, MS4; Anne M. Bowcock, PhD4; Matthew G. Field, MS1,2,3; J. William Harbour, MD1,2,3
[+] Author Affiliations
1Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida
2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
3Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida
4National Heart and Lung Institute, Imperial College of Science and Technology, London, England
JAMA Ophthalmol. 2016;134(7):728-733. doi:10.1001/jamaophthalmol.2016.0903.
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Importance  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.

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

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

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

Results  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).

Conclusions and Relevance  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.

Figures in this Article

Figures

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Figure 1.
Overview of Driver Mutations in Uveal Melanoma, Gene Expression Profile (GEP) Classification, and Metastatic Status in 81 Uveal Melanomas

White boxes indicate mutation absent (wild type); colored boxes, mutation present; and gray box, information not available. For GEP class, blue boxes indicate class 1, and red boxes indicate class 2.

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Figure 2.
Molecular Association Plot Summarizing Statistical Associations Between Driver Mutations

P values indicate statistical significance of association between mutations in 2 genes connected by a given line. Thick orange lines indicate statistically significant inverse associations (P ≤ .05), and gray lines indicate no statistically significant association (P > .05). The thin orange line indicates that mutations in SF3B1 and EIF1AX were almost mutually exclusive, with only one tumor having a mutation in both, but this association did not achieve statistical significance (P = .17).

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