恶性和正常睫状体黑素细胞的多组学比较揭示了睫状体黑色素瘤的分子特征。
Multi-omics comparison of malignant and normal uveal melanocytes reveals molecular features of uveal melanoma.
发表日期：2023 Sep 13
作者：
David Gentien, Elnaz Saberi-Ansari, Nicolas Servant, Ariane Jolly, Pierre de la Grange, Fariba Némati, Géraldine Liot, Simon Saule, Aurélie Teissandier, Deborah Bourc'his, Elodie Girard, Jennifer Wong, Julien Masliah-Planchon, Erkan Narmanli, Yuanlong Liu, Emma Torun, Rebecca Goulancourt, Manuel Rodrigues, Laure Villoing Gaudé, Cécile Reyes, Matéo Bazire, Thomas Chenegros, Emilie Henry, Audrey Rapinat, Mylene Bohec, Sylvain Baulande, Radhia M'kacher, Eric Jeandidier, André Nicolas, Giovanni Ciriello, Raphael Margueron, Didier Decaudin, Nathalie Cassoux, Sophie Piperno-Neumann, Marc-Henri Stern, Johan Harmen Gibcus, Job Dekker, Edith Heard, Sergio Roman-Roman, Joshua J Waterfall
来源：
Cell Reports
摘要：
豆状核黑色素瘤（UM）是源自豆状核黑色素细胞转化的罕见癌症。综合分析已经确定了UM的四个分子和临床亚型。为了提高我们对UM的分子认识，我们进行了广泛的多组学特征比较，将两个进展迅速的UM患者衍生的异种移植模型与正常的脉络膜黑色素细胞进行了比较。我们采用DNA光学图谱、特定的组蛋白修饰以及Hi-C进行了DNA拓扑分析。我们的基因表达和细胞遗传学分析表明，基因组不稳定性是UM的一个特征。我们还发现BAP1启动子中的重复缺失导致表达的丧失，并与UM患者的高转移风险相关。Hi-C揭示了染色质拓扑变化，与UM中独立的预后生物标志物PRAME的上调和潜在治疗靶点相关。我们的发现说明多组学方法在提高我们对肿瘤发生机制的认识方面的作用，并揭示了UM中两种不同的基因表达失调机制。版权所有 © 2023 作者。Elsevier Inc.保留所有权利。
Uveal melanoma (UM) is a rare cancer resulting from the transformation of melanocytes in the uveal tract. Integrative analysis has identified four molecular and clinical subsets of UM. To improve our molecular understanding of UM, we performed extensive multi-omics characterization comparing two aggressive UM patient-derived xenograft models with normal choroidal melanocytes, including DNA optical mapping, specific histone modifications, and DNA topology analysis using Hi-C. Our gene expression and cytogenetic analyses suggest that genomic instability is a hallmark of UM. We also identified a recurrent deletion in the BAP1 promoter resulting in loss of expression and associated with high risk of metastases in UM patients. Hi-C revealed chromatin topology changes associated with the upregulation of PRAME, an independent prognostic biomarker in UM, and a potential therapeutic target. Our findings illustrate how multi-omics approaches can improve our understanding of tumorigenesis and reveal two distinct mechanisms of gene expression dysregulation in UM.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.