title: Somatic genomic alterations in retinoblastoma beyond RB1 are rare and limited to copy number changes.
abstract: Retinoblastoma is a rare childhood cancer initiated by RB1 mutation or MYCN amplification, while additional alterations may be required for tumor development. However, the view on single nucleotide variants is very limited. To better understand oncogenesis, we determined the genomic landscape of retinoblastoma. We performed exome sequencing of 71 retinoblastomas and matched blood DNA. Next, we determined the presence of single nucleotide variants, copy number alterations and viruses. Aside from RB1, recurrent gene mutations were very rare. Only a limited fraction of tumors showed BCOR (7/71, 10%) or CREBBP alterations (3/71, 4%). No evidence was found for the presence of viruses. Instead, specific somatic copy number alterations were more common, particularly in patients diagnosed at later age. Recurrent alterations of chromosomal arms often involved less than one copy, also in highly pure tumor samples, suggesting within-tumor heterogeneity. Our results show that retinoblastoma is among the least mutated cancers and signify the extreme sensitivity of the childhood retina for RB1 loss. We hypothesize that retinoblastomas arising later in retinal development benefit more from subclonal secondary alterations and therefore, these alterations are more selected for in these tumors. Targeted therapy based on these subclonal events might be insufficient for complete tumor control.
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081BT, Amsterdam, The Netherlands.
authors.forename: Irsan E
authors.initials: IE
authors.lastname: Kooi
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081BT, Amsterdam, The Netherlands.
authors.forename: Berber M
authors.initials: BM
authors.lastname: Mol
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3508 AB, Utrecht, The Netherlands.
authors.forename: Maarten P G
authors.initials: MP
authors.lastname: Massink
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081BT, Amsterdam, The Netherlands.
authors.forename: Najim
authors.initials: N
authors.lastname: Ameziane
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081BT, Amsterdam, The Netherlands.
authors.forename: Hanne
authors.initials: H
authors.lastname: Meijers-Heijboer
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081BT, Amsterdam, The Netherlands.
authors.forename: Charlotte J
authors.initials: CJ
authors.lastname: Dommering
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081BT, Amsterdam, The Netherlands.
authors.forename: Saskia E
authors.initials: SE
authors.lastname: van Mil
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081BT, Amsterdam, The Netherlands.
authors.forename: Yne
authors.initials: Y
authors.lastname: de Vries
authors.affiliation: Department of Genetics, University Medical Centre Groningen, University of Groningen, 9700 RB, Groningen, The Netherlands.
authors.forename: Annemarie H
authors.initials: AH
authors.lastname: van der Hout
authors.affiliation: Department of Pediatric Oncology/Hematology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.affiliation: Department of Ophthalmology, VU University Medical Center, de Boelelaan 1117, 1007 MB, Amsterdam, The Netherlands.
authors.forename: Annette C
authors.initials: AC
authors.lastname: Moll
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081BT, Amsterdam, The Netherlands.|Division of Biological Stress Response, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
authors.forename: Hein
authors.initials: H
authors.lastname: Te Riele
authors.affiliation: Department of Pediatric Oncology/Hematology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.|Department of Hematology, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cloos
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081BT, Amsterdam, The Netherlands.
authors.forename: Josephine C
authors.initials: JC
authors.lastname: Dorsman
mesh_terms: D018628:Gene Dosage; D006801:Humans; D009154:Mutation; D012175:Retinoblastoma / Q000473:pathology*; D056286:Retinoblastoma Binding Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; D044767:Ubiquitin-Protein Ligases