Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
Ophthalmic Oncology Service and.
JCI Insight. 2022 May 9;7(9):e147172. doi: 10.1172/jci.insight.147172.
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.
葡萄膜黑色素瘤（UM）是一种独特的疾病，因为原发性 UM 患者根据其发生转移的风险进行了很好的分层，而一旦发生转移，有效的治疗方法却很有限。迫切需要更好地了解 UM 的独特分子发病机制和具有高转移风险的患者特征，以确定可用于免疫治疗的新抗原靶点，并开发可能有效靶向这种致命转变的新治疗策略。UM 中的人类内源性逆转录病毒（HERV）的分子发病机制和新抗原靶点是一个重要且被忽视的领域。我们研究了原发性 UM 中的 HERV 表达谱，发现肿瘤分为 4 种基于 HERV 的亚组，这些亚组明确划分了风险结果，并支持其他分子指标确定的亚型。特定的 HERV 基因座与葡萄膜黑色素瘤转移的风险相关，可能为该过程提供机制上的见解，包括染色体 3 和 8 上 HERV 的失调。由 17 个基因座组成的 HERV 特征足以根据亚型对肿瘤进行分类，准确率超过 95%，其中至少有 1 个具有编码潜力的基因间 HERV（HERVE_Xp11.23），它可能代表免疫治疗的潜在 HERV E 靶点。
