目的：利用生物信息学方法分析与葡萄膜恶性黑色素瘤转移相关的非编码RNA，以及它们作为竞争性内源RNA的作用机制。方法：从癌症基因组图谱(The Cancer Genome Atlas，TCGA)数据库下载80例葡萄膜恶性黑色素瘤患者的RNA测序数据和临床资料，采用edgeR算法分析转移与非转移患者组织中差异表达(differentially expressed，DE)的长链非编码RNA(lncRNA)、微小RNA(miR)和mRNA，并构建lncRNA-miR-mRNA的竞争性内源RNA(competing endogenous RNA，ceRNA)调控网络，基因富集分析和通路分析研究网络中mRNA的生物学功能。Kaplan-Meier生存曲线分析ceRNA网络中核心RNA与生存率的关系。结果：从发生远处转移的葡萄膜恶性黑色素瘤样本中，共鉴定出346个上调的mRNA，118个下调的miR和45个上调的lncRNA。其中67个mRNA，7个miR和30个lncRNA相互组合形成616个ceRNA单元，并形成了一个具有181条边线ceRNA网络。基因富集分析表明：网络中的mRNA富集在肿瘤生成和转移相关的几个基因本体(Gene Ontology)和信号通路。拓扑分析确定了6个核心lncRNA(LINC00861、LINC02421、BHLHE40-AS1、LINC01252、LINC00513和LINC02389)和3个核心mRNA(UNC5D、BCL11B和MTDH)。 所有核心lncRNA、核心mRNA的表达水平和5个miR(miR-221、miR-222、miR-506、miR-507、miR-876)的表达水平均与总体生存率显着相关(均P<0.05)。结论：本研究揭示了几种lncRNA及其相关的ceRNA网络在葡萄膜恶性黑色素瘤转移中的作用，为进一步研究葡萄膜恶性黑色素瘤的发生和/或转移提供了新的方向。

Objective: To elucidate the expression of long non-coding RNAs (lncRNAs) and their roles as competing endogenous RNAs (ceRNAs) in uveal melanoma (UM) metastasis. Methods: RNA sequencing data and clinical information of 80 patients with UM were obtained from The Cancer Genome Atlas (TCGA) database. Differentially expressed (DE) mRNAs, microRNAs (miR), and lncRNAs between metastatic and non-metastatic individuals with UM were screened using the edgeR algorithm. Gene enrichment analysis was conducted for the DE mRNAs. LncRNA-miR-mRNA regulatory triples and a ceRNA network were constructed. Betweenness centrality was used to screen hub genes and lncRNAs for subnetwork analysis. Kaplan-Meier survival analysis was conducted to explore correlations between the expression of hub RNAs and overall survival in the TCGA UM cohort. Results: A total of 346 upregulated mRNAs, 118 downregulated miRs, and 45 upregulated lncRNAs were identified in samples with systemic metastasis. Among them, 67 mRNAs, 7 miRs, and 30 lncRNAs mapped to 616 ceRNA triples, thus forming an interconnected ceRNA network with 181 edges. Gene enrichment analysis revealed that mRNAs in the network were enriched in multiple gene ontology terms and pathways associated with carcinogenesis and metastasis. Topological analysis identified 6 hub lncRNAs (LINC00861, LINC02421, BHLHE40-AS1, LINC01252, LINC00513, and LINC02389) and 3 hub mRNAs (UNC5D, BCL11B, and MTDH). The expression levels of all hub genes and 5 DEmiRs (miR-221, miR-222, miR-506, miR-507, miR-876) were significantly associated with the overall survival probability. Conclusion: This bioinformatic study revealed the functions of several lncRNAs and their associated ceRNA network in UM metastasis. It provides a novel in silicon evidence for future experimental study on the pathogenesis of systemic metastasis in uveal melanoma, especially from the perspective of non-coding RNA.

目的：探讨眼部转移性透明细胞肾细胞癌(clear-cell renal cell carcinoma，CC-RCC)的临床病理特点。方法：选取复旦大学附属眼耳鼻喉科医院2010年1月至2020年12月收治的5例并经病理学检查证实的眼部转移性CC-RCC患者的临床病理资料，包括病史、临床表现、影像学检查、病理形态学特点、免疫表型及随访结果等，并进行回顾分析。结果：5例患者中3例为脉络膜转移性CC-RCC，均为男性，年龄51~62岁，均表现为右眼前黑影伴视力下降，病程为1~6个月，术前检查视力均为眼前手动，眼底见视网膜下隆起肿块伴视网膜脱离。B超显示球内隆起肿物，中等回声，考虑脉络膜黑色素瘤。其中例2在2年前有左侧肾CC-RCC切除病史，术后1年转移至肺。3例患者均行眼球摘除加义眼座植入术。病理学形态及免疫组织化学染色结果提示为球内恶性肿瘤，考虑转移性CC-RCC，建议在肾等处寻找原发灶。术后例1腹部CT检查发现左肾占位，考虑肾癌。胸部CT检查示两下肺多个转移瘤。例3术后PET-CT发现左肾占位，手术切除后证实为左肾CC-RCC。2例为眼眶转移性CC-RCC，例4为女性，56岁，右眼红肿伴眼球突出2个月，2个月前行右肾CC-RCC切除术，PEC-CT提示右侧眼眶转移伴骨质破坏。例5为男性，65岁，左眼眉弓处肿物3年，7年前行左肾癌摘除术，后肺部转移。所有5例患者手术切除标本病理学检查均示肿瘤细胞细胞质透明或颗粒状，呈实性片状和腺样分布，间质血管丰富，免疫组织化学表达CK、VIM、CD10和PAX-8等标记提示CC-RCC转移。结论：CC-RCC可以转移至脉络膜或眼眶，病理学上需要和其他眼部具有透明细胞特征的原发和转移性肿瘤相鉴别。

Objective: To evaluate the clinicopathological features of ocular metastatic clear-cell renal cell carcinoma.Methods: Data of 5 patients (5 eyes) with ocular metastatic clear-cell renal cell carcinoma treated and diagnosed at Eye & ENT Hospital of Fudan University from January 2010 to December 2020 were retrospectively analyzed for medical history, clinical features, imaging examinations, pathomorphological features, immunophenotypes and survival outcomes. Results: There were 3 males of choroidal metastatic clear-cell renal cell carcinoma with age from 51 to 62 years old. They all presented with shadow before the eye and reduced visual acuity of the right eye for 1 to 6 months. On examination the visual acuity was hand movement in front of the affected eye. Fundus examination showed a subretinal elevated mass with retinal detachment. B-scan ultrasound demonstrated an intraocular mass with medium internal reflectivity suspected of choroidal melanoma. Case 2 reported a history of clear-cell renal cell carcinoma treated with a left nephrectomy 2 years ago and developed lung metastasis 1 year ago. Three patients all underwent enucleation and prosthesis implantation. Histopathological and immunohistochemical examinations showed intraocular malignant tumor suggestive of clear-cell renal cell carcinoma which needed further examinations to confirm the primary tumor. Postoperative computed tomography scan of the abdomen for case 1 revealed a mass of the left kidney highly suggestive of a renal cell carcinoma. The computed tomography scan of the chest revealed multiple lesions suggestive of lung metastasis. Postoperative PET-CT scan of case 3 revealed a mass of the left kidney which was confirmed to be clear-cell renal cell carcinoma histopathologically. There were 2 patients of orbital metastatic clear-cell renal cell carcinoma. One 56-year-old female patient (Case 4) presented with swelling, redness and proptosis of the right eye for 2 months. Two months ago, her right kidney was resected for the diagnosis of clear-cell renal cell carcinoma. PEC-CT revealed metastasis to the right orbit with bone destruction. Another 65-year-old male patient (Case 5) presented with palpable mass of the left eyebrow for 3 years. He had left nephrectomy for renal cell carcinoma 7 years earlier and metastasis to the lung later. Histopathology of all 5 cases demonstrated uniform cells with clear or granular cytoplasm in solid and glandular arrangement surrounded by a rich vascular network. Immunohistochemical positivity for the biomarkers CK, Vimentin, CD10 and PAX-8 confirmed the diagnosis of metastatic clear-cell renal cell carcinoma.Conclusion: Clear-cell renal cell carcinoma can metastasize to the choroid or orbit. It should be differentiated from the other ocular primary and metastatic tumors with clear-cell appearance histopathologically.