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Brief Report
March 19, 2020

Genomic and Transcriptomic Tumor Heterogeneity in Bilateral Retinoblastoma

Author Affiliations
  • 1Precision Medicine, Hospital de Pediatría J.P. Garrahan, Buenos Aires, Argentina
  • 2National Scientific and Technical Research Council, CONICET, Buenos Aires, Argentina
  • 3Laboratory of Molecular and Cellular Therapy, Instituto Leloir, Buenos Aires, Argentina
  • 4Centre National de la Recherche Scientifique, Unité Mixte de Recherche 144, Institut Curie, Paris, France
  • 5Pathology Service, Hospital de Pediatría J.P. Garrahan, Buenos Aires, Argentina
  • 6Ophthalmology Service, Hospital de Pediatría J.P. Garrahan, Buenos Aires, Argentina
  • 7Oncology Service, Hospital de Pediatría J.P. Garrahan, Buenos Aires, Argentina
  • 8Centro de Investigaciones Inmunológicas Básicas y Aplicadas, School of Medical Sciences, Universidad de La Plata, La Plata, Argentina
  • 9Soins, Innovation, Recherche, en Oncologie de l’Enfant, de l’Adolescent et de l’Adulte Jeune (SIREDO) Oncology Center, Institut Curie, Paris, France
  • 10Preclinical Therapeutics and Drug Delivery Research Program and Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Deu, Barcelona, Spain
  • 11Centre de Recherche des Cordeliers, Sorbonne Universités, Institut National de la Santé et de la Recherche Médicale, Paris, France
  • 12Functional Genomics of Solid Tumor, Labex Immuno-Oncology, Équipe Labellisée Ligue Contre le Cancer, Université de Paris, Université Paris 13, Paris, France
JAMA Ophthalmol. 2020;138(5):569-574. doi:10.1001/jamaophthalmol.2020.0427
Key Points

Question  Do both ocular tumors of patients with bilateral retinoblastoma show similar genomic and gene expression features?

Findings  In this case report, 2 patients with bilateral retinoblastoma showed eye tumors with distinctive genomic profiles; chromosomal alteration profile supported the origin of the orbital recurrence from the homolateral eye in 1 patient, and in this case, 11q loss may be associated with extraocular relapse. Transcription factor pathways were differentially expressed between the left-eye and right-eye tumors in the second patient.

Meaning  These 2 cases suggest genomic and gene expression differences between tumors in patients with bilateral disease and confirm intereye tumor heterogeneity that might be considered with targeted therapies.


Importance  Comprehensive understanding of the genomic and gene-expression differences between retinoblastoma tumors from patients with bilateral disease may help to characterize risk and optimize treatment according to individual tumor characteristics.

Objective  To compare the genomic features between each eye and a specimen from an orbital relapse in patients with bilateral retinoblastoma.

Design, Setting, and Participants  In this case, 2 patients with retinoblastoma underwent upfront bilateral enucleation. Tumor samples were subjected to genomic and gene-expression analysis. Primary cell cultures were established from both of the tumors of 1 patient and were used for gene-expression studies.

Main Outcomes and Measures  Whole-exome sequencing was performed on an Illumina platform for fresh tumor samples and DNA arrays (CytoScan or OncoScan) were used for paraffin-embedded samples and cell lines. Gene-expression analysis was performed using Agilent microarrays. Germinal and somatic alterations, copy number alterations, and differential gene expression were assessed.

Results  After initial bilateral enucleation, patient 1 showed massive choroidal and laminar optic nerve infiltration, while patient 2 showed choroidal and laminar optic nerve invasion. Patient 1 developed left-eye orbital recurrence and bone marrow metastasis less than 1 year after enucleation. Both ocular tumors showed gains on 1q and 6p but presented other distinct genomic alterations, including an additional gain in 2p harboring the N-myc proto-oncogene (MYCN) in the left tumor and orbital recurrence. Similar copy number alterations between the orbital recurrence and the left eye supported the origin of the relapse, with an additional 11q loss only detected in the orbital relapse. Specimens from patient 2 showed common copy number gains and losses, but further evolution rendered a 2p gain spanning MYCN in the left tumor. For this patient, microarray expression analysis showed differential expression of the MYCN and the forkhead box protein G1 (FOXG1) gene pathways between the left and right tumors.

Conclusions and Relevance  Differential genomic and gene expression features were observed between tumors in 2 patients with bilateral disease, confirming intereye heterogeneity that might be considered if targeted therapies are used in such patients. Chromosomal alteration profile supported the origin of the orbital recurrence from the homolateral eye in 1 patient. Loss in chromosome 11q may have been associated with extraocular relapse in this patient.

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