Recurrent Somatic Chromosomal Abnormalities in Relapsed Extraocular Retinoblastoma.

Guillermo Chantada ,Jasmine H Francis,Soledad Gómez-González ,François Doz,Jaume Mora,Genoveva Correa Llano,Claudia Sampor,Daniela Ottaviani,Santiago Zugbi,Lauriane Lemelle,Marcela Mena,Daiana Ganiewich,Irene Szijan,Fabiana Lubieniecki,Andrea S Llera,Ursula Winter,Cinzia Lavarino,Paula Schaiquevich ,François Radvanyi,Gabriela Lamas,Rosario Aschero,David H Abramson,Osvaldo L Podhajcer

doi:10.3390/cancers13040673

Abstract

Simple SummaryRelapse outside the eye of retinoblastoma (the most common eye cancer in children) is an uncommon event in developed countries, however it is the main cause of death in patients with retinoblastoma worldwide. The genomic features of this population are not known. We studied 23 cases from four countries and found a characteristic pattern in chromosomal copy number alterations that could help guide future clinical management of these patients.Most reports about copy number alterations (CNA) in retinoblastoma relate to patients with intraocular disease and features of children with extraocular relapse remain unknown, so we aimed to describe the CNA in this population. We evaluated 23 patients and 27 specimens from 4 centers. Seventeen cases had extraocular relapse after initial enucleation and six cases after an initial preservation attempt. We performed an analysis of CNA and BCOR gene alteration by SNP array (Single Nucleotide Polymorfism array), whole-exome sequencing, IMPACT panel and CGH array (Array-based comparative genomic hybridization). All cases presented CNA at a higher prevalence than those reported in previously published studies for intraocular cases. CNA previously reported for intraocular retinoblastoma were found at a high frequency in our cohort: gains in 1q (69.5%), 2p (60.9%) and 6p (86.9%), and 16q loss (78.2%). Other, previously less-recognized, CNA were found including loss of 11q (34.8%), gain of 17q (56.5%), loss of 19q (30.4%) and BCOR alterations were present in 72.7% of our cases. A high number of CNA including 11q deletions, 17q gains, 19q loss, and BCOR alterations, are more common in extraocular retinoblastoma. Identification of these features may be correlated with a more aggressive tumor warranting consideration for patient management.

Highlights

Extraocular relapse of retinoblastoma, either after initial enucleation or an eye preservation attempt is rare in high-income countries, but it is the most common cause of disease-related death from this tumor [1,2]
We found a high frequency of other novel copy number alterations (CNA) which were reported less frequently in intraocular retinoblastoma, such as 17q gains (56.5%, 13/23), 11q loss (34.8%, 8/23), 19q loss (30.4%, 7/23) and 21q loss (26.1%, 6/23)
The median age at diagnosis of our patients with unilateral retinoblastoma having an extraocular relapse after initial enucleation was 33 months which is substantially higher than that previously reported for unilateral disease (22 months in a South American report and 28 months in a recently reported series of patients with high-risk pathology factors (HRPF) and CNA) [3,11]

Summary

Introduction

Extraocular relapse of retinoblastoma, either after initial enucleation or an eye preservation attempt is rare in high-income countries, but it is the most common cause of disease-related death from this tumor [1,2]. The identification of the genomic features of retinoblastoma has focused mostly on intraocular cases and overall genomic features of a limited number of patients with extraocular relapse have been reported in the literature [9,10,11,12,13,14,15,16,17,18,19] In such studies, other recurrent CNA besides the 13q loss or copy-neutral loss of heterozygosity (CN-LOH), such as gains in chromosomes 1q, 6p, 2p and losses in 16q have been identified in intraocular retinoblastoma, but none has been conclusively related to an increased risk of extraocular relapse

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