Abstract

Importance Frequent mutations have been described in the following 5 genes in uveal melanoma (UM):BAP1,EIF1AX,GNA11,GNAQ, andSF3B1. 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%).BAP1mutations were identified in 29 of 64 (45%),GNAQmutations in 36 of 81 (44%),GNA11mutations in 36 of 81 (44%),SF3B1mutations in 19 of 81 (24%), andEIF1AXmutations in 14 of 81 (17%). Sixteen of the mutations inBAP1and 6 of the mutations inEIF1AXwere previously unreported in UM.GNAQandGNA11mutations were mutually exclusive.BAP1,SF3B1, andEIF1AXmutations were almost mutually exclusive with each other. Using multiple regression analysis,BAP1mutations were associated with class 2 GEP and older patient.EIF1AXmutations were associated with class 1 GEP and the absence of ciliary body involvement.SF3B1mutations were associated with younger patient age.GNAQmutations were associated with the absence of ciliary body involvement and greater largest basal diameter.GNA11mutations 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 ofBAP1mutations 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, andEIF1AXmutations 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.