de Lange Mark J, van Pelt Sake I, Versluis Mieke, Jordanova Ekaterina S, Kroes Wilma G M, Ruivenkamp Claudia, van der Burg Sjoerd H, Luyten Grégorius P M, van Hall Thorbald, Jager Martine J, van der Velden Pieter A
Department of Ophthalmology, LUMC, Leiden, The Netherlands.
Department of Pathology, LUMC, Leiden, The Netherlands.
Oncotarget. 2015 Nov 10;6(35):37824-35. doi: 10.18632/oncotarget.5637.
Gene expression profiles as well as genomic imbalances are correlated with disease progression in uveal melanoma (UM). We integrated expression and genomic profiles to obtain insight into the oncogenic mechanisms in development and progression of UM. We used tumor tissue from 64 enucleated eyes of UM patients for profiling. Mutations and genomic imbalances were quantified with digital PCR to study tumor heterogeneity and molecular pathogenesis. Gene expression analysis divided the UM panel into three classes. Class I presented tumors with a good prognosis and a distinct genomic make up that is characterized by 6p gain. The UM with a bad prognosis were subdivided into class IIa and class IIb. These classes presented similar survival risks but could be distinguished by tumor heterogeneity. Class IIa presented homogeneous tumors while class IIb tumors, on average, contained 30% of non-mutant cells. Tumor heterogeneity coincided with expression of a set of immune genes revealing an extensive immune infiltrate in class IIb tumors. Molecularly, class IIa and IIb presented the same genomic configuration and could only be distinguished by 8q copy number. Moreover, UM establish in the void of the immune privileged eye indicating that in IIb tumors the infiltrate is attracted by the UM. Combined our data show that chromosome 8q contains the locus that causes the immune phentotype of UM. UM thereby provides an unique opportunity to study immune attraction by tumors.
基因表达谱以及基因组失衡与葡萄膜黑色素瘤(UM)的疾病进展相关。我们整合了表达谱和基因组谱,以深入了解UM发生发展过程中的致癌机制。我们使用了64例UM患者摘除眼球的肿瘤组织进行分析。通过数字PCR对突变和基因组失衡进行定量,以研究肿瘤异质性和分子发病机制。基因表达分析将UM样本分为三类。I类表现为预后良好且具有独特基因组组成的肿瘤,其特征是6p增益。预后不良的UM被细分为IIa类和IIb类。这两类具有相似的生存风险,但可通过肿瘤异质性区分。IIa类表现为均质肿瘤,而IIb类肿瘤平均含有30%的非突变细胞。肿瘤异质性与一组免疫基因的表达一致,表明IIb类肿瘤中有广泛的免疫浸润。在分子水平上,IIa类和IIb类具有相同的基因组构型,仅可通过8q拷贝数区分。此外,UM在免疫赦免眼的间隙中形成,这表明在IIb类肿瘤中浸润是由UM吸引的。综合我们的数据表明,8号染色体q包含导致UM免疫表型的基因座。因此,UM为研究肿瘤对免疫的吸引提供了独特的机会。