title: Genetic evolution of uveal melanoma guides the development of an inflammatory microenvironment.
abstract: Uveal melanoma (UM) is characterized by a number of genetic aberrations that follow a certain chronology and are tightly linked to tumor recurrence and survival. Loss of chromosome 3, bi-allelic loss of BAP1 expression, and gain in chromosome 8q have been associated with metastasis formation and death, while loss of chromosome 3 has been associated with the influx of macrophages and T cells. We used a set of genetically-classified UM to study immune infiltration in the context of their genetic evolution. We show in two independent cohorts that lack of BAP1 expression is associated with an increased density of CD3+T cells and CD8+T cells. The presence of extra copies of chromosome 8q in disomy 3 tumors with a normal BAP1 expression is associated with an increased influx of macrophages (but not T cells). Therefore, we propose that the genetic evolution of UM is associated with changes in the inflammatory phenotype. Early changes resulting in gain of chromosome 8q may activate macrophage infiltration, while sequential loss of BAP1 expression seems to drive T cell infiltration in UM.
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Gülçin
authors.initials: G
authors.lastname: Gezgin
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Dogrusöz
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: T Huibertus
authors.initials: TH
authors.lastname: van Essen
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Wilhelmina G M
authors.initials: WGM
authors.lastname: Kroes
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Gregorius P M
authors.initials: GPM
authors.lastname: Luyten
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Pieter A
authors.initials: PA
authors.lastname: van der Velden
authors.affiliation: Department of Biochemistry, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Vonn
authors.initials: V
authors.lastname: Walter
authors.affiliation: Department of Pathology, Section Ophthalmic Pathology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Verdijk
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Thorbald
authors.initials: T
authors.lastname: van Hall
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. M.J.Jager@lumc.nl.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Jager
mesh_terms: D002869:Chromosome Aberrations; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D015331:Cohort Studies; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D019143:Evolution, Molecular; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000276:immunology*; D009154:Mutation; D059016:Tumor Microenvironment / Q000235:genetics* / Q000276:immunology; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism; D014604:Uveal Neoplasms / Q000235:genetics* / Q000276:immunology*; D000098943:Uveal Melanoma
chemical_list: C400134:BAP1 protein, human; D016207:Cytokines; D004273:DNA, Neoplasm; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase
keywords: BAP1; Chromosome; Infiltration; Lymphocytes; Macrophages; T cells