Introduction: Uveal melanoma is the most common primary intraocular tumor of the eye and has a propensity for fatal hematogenous metastasis. Gene expression profiling is routinely used in clinic to classify uveal melanoma into prognostic subgroups: Class 1 (low metastatic risk) and Class 2 (high metastatic risk). Approximately 40% of Class 2 patients metastasize, which accounts for 85% of metastasis. The remaining 15% of patients that metastasize are Class 1 based on gene expression profiling, however this study demonstrates that the Class 1 patients that metastasize (Class1met+) can be defined as a new molecular subclass, distinct from Class 1 patients that do not metastasize (Class1met-) and Class 2 patients.
Methods: Tumor samples from Class1met+ and Class1met- patients with at least 1 year of follow-up underwent histopathologic, cytogenetic and transcriptomic analyses.
Results: In a comparison of Class1met+ and Class1met- tumors, the only significant difference was a larger mean basal tumor diameter in Class1met+ tumors. Cytogenetic analyses revealed more extensive copy number gains and losses in Class1met+ tumors. The most significant differentiating features in Class1met+ tumors included 1q gain, 6p gain, 6q loss, and 8q gain. Using principal component analysis, the Class1met+ tumors clustered separately from the Class1met- tumors, indicating the existence of significant transcriptomic differences between the two subgroups. Strikingly, the most highly differentially expressed gene in Class1met+ tumors was preferentially expressed antigen in melanoma (PRAME); mean mRNA expression of PRAME in Class1met+ tumors was 61-fold higher than in Class1met- tumors.
Discussion: We define a new subtype of uveal melanoma and demonstrate that gene expression of PRAME can distinguish between Class1met+ patients and Class1met- patients.
Citation Format: Matthew G. Field, Christina L. Decatur, J. William Harbour. PRAME as a biomarker for a new molecular subclass of uveal melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4262. doi:10.1158/1538-7445.AM2015-4262