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Updated: Mar 22, 2026
Reconstruct Human Retinoblastoma In Vitro
Published on: October 11, 2022
Somatic genomic alterations in retinoblastoma beyond RB1 are rare and limited to copy number changes
Irsan E Kooi1, Berber M Mol1, Maarten P G Massink2
1Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081BT, Amsterdam, The Netherlands.
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.
Insights
Retinoblastoma, a rare childhood cancer, is primarily driven by RB1 gene loss. Other genetic mutations are rare, with copy number alterations playing a more significant role, especially in older patients.
Area of Science:
- Oncology
- Genetics
- Ophthalmology
Background:
- Retinoblastoma is a rare childhood eye cancer initiated by RB1 gene mutations or MYCN amplification.
- Understanding the genomic landscape beyond RB1 is crucial for comprehending retinoblastoma oncogenesis.
Purpose of the Study:
- To determine the genomic landscape of retinoblastoma, focusing on single nucleotide variants and copy number alterations.
- To investigate the role of genetic alterations in retinoblastoma development and their correlation with patient age at diagnosis.
Main Methods:
- Whole exome sequencing of 71 retinoblastoma tumors and matched blood DNA.
- Analysis of single nucleotide variants, copy number alterations, and viral presence.
Main Results:
- Retinoblastoma exhibits a low mutation rate, with RB1 alterations being the primary driver.
- Recurrent mutations in BCOR and CREBBP were infrequent (10% and 4%, respectively).
- Somatic copy number alterations, particularly partial deletions, were more prevalent, especially in tumors from older children, suggesting intra-tumor heterogeneity.
Conclusions:
- Retinoblastoma is one of the least mutated cancers, highlighting the critical role of RB1 loss in retinal development.
- Later-onset retinoblastomas may benefit from subclonal secondary alterations, which are selected for during tumor progression.
- Targeted therapies focusing solely on subclonal events may not be sufficient for complete tumor eradication.
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