Genetic determinants of uveal melanoma

Uveal melanoma (UM) arises from neural crest-derived melanocytes of the choroid and the ciliary body. About 50% of patients develop metastatic disease despite efficient control of the primary tumor. For about 15 years, cytogenetic and, recently, genome-wide analysis techniques have shown that UM can be classified into 2 genomic groups correlating with prognostic clinicopathologic features: class 1 tumors, with a low risk of metastases, typically characterized by a gain of the 6p chromosome arm, often associated with a gain of the distal part of the 8q chromosome arm, and class 2 tumors, with a high metastatic risk, presenting loss of the entire chromosome 3 and gain of the entire 8q, related to the formation of isochromosomes. Genome-wide expression profiling has proved to be a powerful tool for separating these 2 classes. However, despite advances in the genomic and prognostic characterization of UM, the knowledge of pathways deregulated in these tumors is just emerging and, in contrast to cutaneous melanoma, no major predisposing genes are known. Altered or deregulated genes are reviewed in this chapter. Inactivating mutations have recently been identified by exome sequencing in gene BAP1, mapping to 3p21.1, in class 2 tumors. Among other discriminant genes identified from genome-wide expression profiling, PTP4A3, mapping to 8q24.3, coding for a protein promoting cell migration, is highly overexpressed in class 2 tumors. The overall expression signature of class 2 tumors suggests they may originate from neuroectodermal stem cells.