葡萄膜黑色素瘤是成年人最常见的原发性眼内恶性肿瘤。主要频发突变基因为GNAQ，GNA11，BAP1，SF3B1，和EIF1AX。这些频发突变相互关联： GNAQ突变和GNA11突变之间互斥; BAP1突变，SF3B1突变和EIF1AX突变之间互斥; 第一组突变（GNAQ和GNA11）和第二组突变（BAP1，SF3B1和EIF1AX）之间共存。BAP1，SF3B1，和EIF1AX突变之间互斥的机制目前未见报道。我们发现BAP1缺失与SF3B1突变在GNAQ突变的背景下导致合成致衰老。利用合成致死/致病效应开发靶向药物是目前抗肿瘤研究的热点。PARP抑制剂用于BRCA1/2突变的肿瘤患者就是利用合成致死的成功范例。本项目拟以频发突变的互斥模式为切入点，研究BAP1缺失与SF3B1突变合成致衰老的机制，以期为葡萄膜黑色素瘤患者提供新的治疗思路。

Uveal melanoma is the most common primary intraocular malignancy in adults. The most frequently mutated genes that are considered to be drivers in uveal melanoma development and progression are GNAQ, GNA11, BAP1, SF3B1, and EIF1AX. We found that these mutations correlate with each other by analyzing related publications as well as utilizing the large-scale cancer genome sequencing project The Cancer Genome Atlas (TCGA): mutations in GNAQ and GNA11 appear in a mutually exclusive manner; BAP1, SF3B1, and EIF1AX occur in a mutually exclusive manner; group1 (GNAQ and GNA11) and group 2 (BAP1, SF3B1, and EIF1AX) show co-occurrence. The mutual exclusivity between GNAQ and GNA11 is apparent because the similar functions of GNAQ and GNA11. Notably, the mechanisms underlying the mutually exclusive pattern among the mutations of BAP1, SF3B1, and EIF1AX remain unknown. Our preliminary data shows that BAP1 deletion and SF3B1 hotspot mutation induce synthetic senescence on the background of GANQ mutation: both BAP1 knockout in uveal melanoma cells with SF3B1 hotspot mutation and expression of SF3B1 hotspot mutation in uveal melanoma cells with BAP1 deficiency induce cellular senescence. Synthetic lethality/sickness has been of increasing interest as a strategy for cancer therapy, supported by major research investment. The successful example of a synthetic lethal therapy to reach the clinic is the targeting of BRCA1- or BRCA2-deficient tumor cells with PARP (poly (ADP-ribose) polymerase) inhibitors, and this potential success story creates a new paradigm for anticancer drug development. Encouraged by the discovery of the phenotype of synthetic senescence induced by BAP1 deficiency and SF3B1 mutation, we propose to explore the underlying mechanisms. The study aims to offer novel treatment approaches for uveal melanoma.