Recurrent Somatic Chromosomal Abnormalities in Relapsed Extraocular Retinoblastoma

Abstract

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.

Keywords: BCOR mutations; copy number alteration; extraocular retinoblastoma; genomic; metastasis.

Figure 1

Clinical, pathologic, and genetic features of the 23 retinoblastoma patients. Each column represents an individual sample, and the rectangular boxes correspond to the status of each of the main characteristics depicted. Boxes are partitioned if more than one relevant feature coexists. For each clinical feature, the corresponding legend is represented on the left of the figure. For copy number alterations, gains are shown in red, blue represents losses, yellow is for CN-LOH and purple for chromothripsis, while the intensity of the color shade is proportional to the value of the log-ratio (LRR). In addition, full coloring means the copy number alteration comprises the whole segment (>90% of the arm), whereas a circle means part of the segment is altered and a star means it is a focal alteration (<15 genes). In cases where samples from primary site and metastatic site were available (patients RB5, RB11, RB12 and RB18), only the primary tumor results were represented. Abbreviations: CNS: central nervous system. WES: whole-exome sequencing. CN-LOH: copy neutral-loss of heterozygosity. ADF: alive disease free.

Figure 2

Significantly altered copy number regions identified by GISTIC. A karyogram overview of the cumulative copy number is shown separately for gains (red) and losses (blue) across the genome, depicted in the y-axis. In the x-axis, the GISTIC q-values are shown on a log scale and the green line represents the significance threshold (q-value = 0.25). Significantly altered regions are mentioned on the sides. For this analysis, samples from Hospital Garrahan and Sant Joan de Deu were used. In cases where samples from primary site and metastatic site were available (patients RB5, RB11, RB12 and RB18), only the primary tumor results were considered.

Figure 3

Landscape of somatic alterations in paired primary tumor metastatic site samples from retinoblastoma patients.