A Meta-Analysis of Retinoblastoma Copy Numbers Refines the List of Possible Driver Genes Involved in Tumor Progression.
While RB1 loss initiates retinoblastoma development, additional somatic copy number alterations (SCNAs) can drive tumor progression. Although SCNAs have been identified with good concordance between studies at a cytoband resolution, accurate identification of single genes for all recurrent SCNAs is still challenging. This study presents a comprehensive meta-analysis of genome-wide SCNAs integrated with gene expression profiling data, narrowing down the list of plausible retinoblastoma driver genes.



We performed SCNA profiling of 45 primary retinoblastoma samples and eight retinoblastoma cell lines by high-resolution microarrays. We combined our data with genomic, clinical and histopathological data of ten published genome-wide SCNA studies, which strongly enhanced the power of our analyses (N = 310).



Comprehensive recurrence analysis of SCNAs in all studies integrated with gene expression data allowed us to reduce candidate gene lists for 1q, 2p, 6p, 7q and 13q to a limited gene set. Besides the well-established driver genes RB1 (13q-loss) and MYCN (2p-gain) we identified CRB1 and NEK7 (1q-gain), SOX4 (6p-gain) and NUP205 (7q-gain) as novel retinoblastoma driver candidates. Depending on the sample subset and algorithms used, alternative candidates were identified including MIR181 (1q-gain) and DEK (6p gain). Remarkably, our study showed that copy number gains rarely exceeded change of one copy, even in pure tumor samples with 100% homozygosity at the RB1 locus (N = 34), which is indicative for intra-tumor heterogeneity. In addition, profound between-tumor variability was observed that was associated with age at diagnosis and differentiation grades.



Since focal alterations at commonly altered chromosome regions were rare except for 2p24.3 (MYCN), further functional validation of the oncogenic potential of the described candidate genes is now required. For further investigations, our study provides a refined and revised set of candidate retinoblastoma driver genes.
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
Irsan E
IE
Kooi
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
Berber M
BM
Mol
Department of Bio-medical Genetics, University Medical center Utrecht, Utrecht, The Netherlands.
Maarten P G
MP
Massink
Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
Marcus C
MC
de Jong
Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
Pim
P
de Graaf
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Paul
P
van der Valk
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
Hanne
H
Meijers-Heijboer
Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.
Gertjan J L
GJ
Kaspers
Department of Ophthalmology, VU University Medical Center, Amsterdam, the Netherlands.
Annette C
AC
Moll
Division of Biological Stress Response, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Hein
H
Te Riele
Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
Jacqueline
J
Cloos
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
Josephine C
JC
Dorsman
D045744:Cell Line, Tumor; D018450:Disease Progression; D018628:Gene Dosage; D020869:Gene Expression Profiling; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D019572:Retinal Neoplasms / Q000235:genetics*; D012175:Retinoblastoma / Q000235:genetics*; D056286:Retinoblastoma Binding Proteins / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; D044767:Ubiquitin-Protein Ligases