title: Heterogeneity revealed by integrated genomic analysis uncovers a molecular switch in malignant uveal melanoma.
abstract: 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.
authors.affiliation: Department of Ophthalmology, LUMC, Leiden, The Netherlands.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: de Lange
authors.affiliation: Department of Ophthalmology, LUMC, Leiden, The Netherlands.
authors.forename: Sake I
authors.initials: SI
authors.lastname: van Pelt
authors.affiliation: Department of Ophthalmology, LUMC, Leiden, The Netherlands.
authors.forename: Mieke
authors.initials: M
authors.lastname: Versluis
authors.affiliation: Department of Pathology, LUMC, Leiden, The Netherlands.
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.affiliation: Department of Clinical Genetics Laboratory for Diagnostic Genome Analysis (LDGA), LUMC, Leiden, The Netherlands.
authors.forename: Wilma G M
authors.initials: WG
authors.lastname: Kroes
authors.affiliation: Department of Clinical Genetics Laboratory for Diagnostic Genome Analysis (LDGA), LUMC, Leiden, The Netherlands.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ruivenkamp
authors.affiliation: Department of Clinical Oncology, LUMC, Leiden, The Netherlands.
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
authors.affiliation: Department of Ophthalmology, LUMC, Leiden, The Netherlands.
authors.forename: Grégorius P M
authors.initials: GP
authors.lastname: Luyten
authors.affiliation: Department of Clinical Oncology, LUMC, Leiden, The Netherlands.
authors.forename: Thorbald
authors.initials: T
authors.lastname: van Hall
authors.affiliation: Department of Ophthalmology, LUMC, Leiden, The Netherlands.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Jager
authors.affiliation: Department of Ophthalmology, LUMC, Leiden, The Netherlands.
authors.forename: Pieter A
authors.initials: PA
authors.lastname: van der Velden
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics; D020869:Gene Expression Profiling; D023281:Genomics / Q000379:methods*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D014604:Uveal Neoplasms / Q000235:genetics* / Q000473:pathology; D055815:Young Adult; D000098943:Uveal Melanoma
chemical_list: D014408:Biomarkers, Tumor; C554062:GNA11 protein, human; D044385:GTP-Binding Protein alpha Subunits
keywords: digital PCR; immune profile; molecular etiology; tumor heterogeneity; uveal melanoma