Heterogeneity revealed by integrated genomic analysis uncovers a molecular switch in malignant uveal melanoma
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Mark J. de Lange1, Sake I. van Pelt1, Mieke Versluis1, Ekaterina S. Jordanova2, Wilma G.M. Kroes3, Claudia Ruivenkamp3, Sjoerd H. van der Burg4, Grégorius P.M. Luyten1, Thorbald van Hall4, Martine J. Jager1, Pieter A. van der Velden1
1Department of Ophthalmology, LUMC, Leiden, The Netherlands
2Department of Pathology, LUMC, Leiden, The Netherlands
3Department of Clinical Genetics Laboratory for Diagnostic Genome Analysis (LDGA), LUMC, Leiden, The Netherlands
4Department of Clinical Oncology, LUMC, Leiden, The Netherlands
Pieter A. van der Velden, e-mail: firstname.lastname@example.org
Keywords: uveal melanoma, tumor heterogeneity, digital PCR, immune profile, molecular etiology
Received: April 15, 2015 Accepted: September 28, 2015 Published: October 08, 2015
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.
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