Genetic Analysis of Uveal Melanoma in 658 Patients Using the Cancer Genome Atlas Classification of Uveal Melanoma as A, B, C, and D Pornpattana Vichitvejpaisal, MD, 1,2 Lauren A. Dalvin, MD, 1,3 Mehdi Mazloumi, MD, MPH, 1 Kathryn G. Ewens, PhD, 4 Arupa Ganguly, PhD, 4 Carol L. Shields, MD 1 Purpose: The Cancer Genome Atlas (TCGA) classification has been validated for uveal melanoma (UM) prognostication. We applied TCGA classification to UM biopsied using fine-needle aspiration biopsy (FNAB) to determine the predictability for metastasis and death. Design: Retrospective cohort study. Participants: Patients with UM treated with plaque radiotherapy at Wills Eye Hospital, Philadelphia, Penn- sylvania, from October 1, 2008, through December 31, 2018, who completed genetic analysis of chromosomes 3 and 8 after FNAB. Methods: Tumors were classified as A, B, C, or D and were compared using the chi-square test, Fisher exact test, analysis of variance, and Kaplan-Meier analysis. Main Outcome Measures: Metastasis and death. Results: Six hundred fifty-eight UM patients were categorized accordingly as TCGA class A (n ¼ 342 [52%]), B (n ¼ 91 [14%]), C (n ¼ 118 [18%]), and D (n ¼ 107 [16%]). More advanced tumor classification revealed older mean patient age (56 vs. 53 vs. 60 vs. 63 years, respectively; P < 0.001), worse presenting visual acuity (20/20e20/50: 81% vs. 67% vs. 71% vs. 66%, respectively; P < 0.001), greater distance from the optic disc (3.5 vs. 4.9 vs. 5.7 vs. 5.3 mm, respectively; P < 0.001), larger tumor basal diameter (10.3 vs. 12.9 vs. 13.9 vs. 15.3 mm, respectively; P < 0.001), and greater tumor thickness (4.3 vs. 6.1 vs. 6.6 vs. 7.5 mm, respectively; P < 0.001). After mean follow-up (47.6 vs. 47.6 vs. 42.9 vs. 28.7 months, respectively; P < 0.001), more advanced TCGA class was associated with increased risk of metastasis (3% vs. 10% vs. 25% vs. 41%, respectively; P < 0.001) and death (1% vs. 0% vs. 3% vs. 9%, respectively; P < 0.001). Compared with class A, the 5-year hazard ratio for metastasis increased at 4.1 (B vs. A; P ¼ 0.01), 10.1 (C vs. A; P < 0.001), and 30.0 (D vs. A; P < 0.001). The 5-year hazard ratio for death increased at 3.1 (C vs. A; P ¼ 0.11) and 13.7 (D vs. A; P < 0.001) with no deaths in class B. Conclusions: Grouping of UM using TCGA classification predicts the risk of melanoma-related metastasis and death. Ophthalmology 2019;-:1e9 ª 2019 by the American Academy of Ophthalmology Uveal melanoma (UM) is the most common primary intra- ocular malignancy of adulthood, with numerous documented clinical, histopathologic, and genetic prognosticators. 1,2 Despite refinement in the management of UM over the past decade, the mortality rate has remained disturbingly high. 3 Understanding that nearly 50% of affected patients eventually will demonstrate metastasis highlights the importance of early detection at a point when the tumor is small and the genetic profile is more favorable. 2,4 Such pa- tients potentially could benefit from early intervention to reduce tumor de-differentiation into a more malignant process. 5 Genetic testing using fine-needle aspiration biopsy (FNAB) has earned a fundamental role in modern manage- ment of UM. 6 This tumor analysis has evolved over the past 2 decades from single chromosome 3 analysis to multiple gene analyses of chromosomes 1, 3, 6, and 8, gene expression profiling, or a combination thereof. 2,7e10 Most of the avail- able studies in the literature have proven that loss of 1 chro- mosome 3 and addition of copies of 8q in UM cells are associated with an increased risk of metastasis. 11 Shields et al 12 recently determined the personalized risk of UM- related metastasis based on all possible arrays of chromo- somes 3 (p and q arms), 6 (p and q arms), and 8 (p and q arms) using Kaplan-Meier analysis, revealing 5-year estimates of metastasis ranging from 4% for those with chromosomes 3, 6, and 8 disomy up to 39% for those with chromosome 3 com- plete monosomy, chromosome 6 disomy, and chromosome 8q gain. However, correlating and understanding the details of each chromosomal profile can be tedious. The Cancer Genome Atlas (TCGA) is a project started in 2005 and supervised by the National Cancer Institute’s 1 ª 2019 by the American Academy of Ophthalmology Published by Elsevier Inc. https://doi.org/10.1016/j.ophtha.2019.04.027 ISSN 0161-6420/19