Specific human endogenous retroviruses predict metastatic potential in uveal melanoma

Uveal melanoma (UM) is a unique disease in that patients with primary UM are well stratified based on their risk of developing metastasis, yet there are limited effective treatments once metastases occur. There is an urgent need to better understand the distinct molecular pathogenesis of UM and the characteristics of patients at high risk for metastasis to identify neoantigenic targets that can be used in immunotherapy and to develop novel therapeutic strategies that may effectively target this lethal transition. An important and overlooked area of molecular pathogenesis and neoantigenic targets in UM comes from human endogenous retroviruses (HERVs). We investigated the HERV expression landscape in primary UM and found that tumors were stratified into 4 HERV-based subsets that provide clear delineation of risk outcome and support subtypes identified by other molecular indicators. Specific HERV loci are associated with the risk of uveal melanoma metastasis and may offer mechanistic insights into this process, including dysregulation of HERVs on chromosomes 3 and 8. A HERV signature composed of 17 loci was sufficient to classify tumors according to subtype with greater than 95% accuracy, including at least 1 intergenic HERV with coding potential (HERVE_Xp11.23) that could represent a potential HERV E target for immunotherapy.