Metabolomic and miRNA profiling of vitreous humor in uveal melanoma

项目摘要/摘要 眼睛的葡萄膜束(虹膜、睫状体和脉络膜)含有黑素细胞，可发展为黑色素瘤。 葡萄膜黑色素瘤(UM)虽然罕见，约占所有黑色素瘤的5%，但仍是最常见的 成人常见的原发眼内癌。UM是一种高度侵袭性的癌症， 有很强的转移倾向，通常转移到肝脏。目前，对于转移性UM还没有有效的治疗方法， 在大多数情况下，这会导致不到一年的死亡。然而，正在进行的临床试验提供了一些希望 辅助治疗和更好地管理转移疾病的有希望的结果；因此是有效的 预测和最佳监测仍然至关重要。一种商业预后测试，目前可用于 UM涉及原发肿瘤样本的基因表达谱(GEP)，通常通过细针获得 常用保眼近距离放射治疗前抽吸活组织检查。GEP确定了两个主要的预后因素 类别(1类为低转移风险，2类为高转移风险)；然而，1类肿瘤患者可能 仍然会发生转移。此外，由于众所周知的与肿瘤活检相关的问题/关切， 在原发UM中，仍然需要更准确和无肿瘤活检(基于生物流体)的预后检测。 鉴于UM主要累及眼后段的脉络膜(~90%)，填充的玻璃体体液 后眼腔，构成了基于生物流体的UM生物标志物开发的极佳候选者。 与可能受多种因素/条件影响的体液不同，玻璃体的成分 主要反映/反映局部眼睛环境。癌症具有代谢性和表观遗传学的特征 重新编程以及近年来出现了与癌症相关的代谢和表观遗传扰动 作为新的潜在生物标志物和治疗靶点。据我们所知，与UM相关的代谢组学研究 缺乏和玻璃体miRNA的研究非常有限。考虑到该技术的可行性和潜在的临床应用价值 生物体液的小分子(代谢物和miRNA)图谱，我们建议全面检查 UM患者的玻璃体代谢物和miRNAs，以探讨玻璃体侧写对 区分不同的UM预后亚型，并利用我们的发现：(I)提高我们对UM预后的理解 UM生物学背后的分子扰动，(Ii)揭示未来UM的新潜在生物标记物 改善预后的努力，以及(Iii)发现未来临床干预的新治疗靶点。 我们的初步代谢组学数据支持玻璃体侧写的潜在用途 UM亚型之间的差异，也暗示了一些新的有趣的生物学途径/机制。因此， 我们的研究结果有望促进我们对UM的了解，并成为迈向以下目标的重要第一步 改善UM的诊断、预测和管理。

PROJECT SUMMARY / ABSTRACT The uveal tract (iris, ciliary body, and choroid) of the eye contains melanocytes and can develop melanoma. Although overall rare, accounting for about 5% of all melanomas, uveal melanoma (UM) represents the most common primary intraocular cancer observed in adult population. UM is a highly aggressive cancer with a strong propensity to metastasize, often to the liver. Currently, there is no effective therapy for metastatic UM, which leads to death in less than a year in most cases. Ongoing clinical trials, however, provide some hope with promising results for adjuvant therapy and better management of metastatic disease; hence effective prognostication and optimal surveillance remain essential. A commercial prognostic test currently available for UM involves gene expression profiling (GEP) of primary tumor samples, often obtained by fine-needle aspiration biopsy prior to commonly used eye-preserving brachytherapy. GEP identifies two major prognostic categories (class 1 with low and class 2 with high metastatic risk); however, patients with class 1 tumors may still develop metastases. Moreover, because of well-known tumor biopsy-related issues/concerns, there remains a need for a more accurate and tumor biopsy-free (biofluid-based) prognostic testing in primary UM. Given that UM predominantly involves the choroid at posterior eye segment (~90%), the vitreous humor that fills the posterior eye cavity, constitutes an excellent candidate for biofluid-based UM biomarker development. Unlike the systemic fluids, which can be affected by multiple factors/conditions, the vitreous' composition predominantly reflects/mirrors local eye environment. Cancer has the hallmarks of metabolomic and epigenetic reprogramming and, in recent years, cancer-associated metabolic and epigenetic perturbations have emerged as new potential biomarkers and therapeutic targets. To our knowledge, UM-related metabolomics studies are lacking and vitreous miRNA studies are very limited. Considering the feasibility and potential clinical utility of small molecule (metabolite and miRNA) profiling of biofluids, we propose to comprehensively examine the vitreous metabolites and miRNAs in UM patients in order to investigate the potential utility of vitreous profiling to distinguish different UM prognostic subtypes and utilize our findings to (i) advance our understanding of molecular perturbations underlying the UM biology, (ii) unravel new potential biomarkers for future UM prognostication improvement efforts, and (iii) uncover new therapeutic targets for future clinical interventions. Our preliminary metabolomics data provide support for potential utility of vitreous profiling to distinguish between UM subtypes and also implicate some new intriguing biological pathways/mechanisms. Hence, the results of our study are expected to advance our knowledge of UM and serve as an essential first step towards improving the UM diagnosis, prognostication, and management.