Molecular Changes in Retinoblastoma beyond RB1: Findings from Next-Generation Sequencing

Jasmine H Francis,Diana L Mandelker,Michael F Berger,David H Abramson,Ira J Dunkel,Allison L Richards,Mark T A Donoghue,Michael F Walsh

doi:10.3390/cancers13010149

Abstract

This investigation uses hybridization capture-based next-generation sequencing to deepen our understanding of genetics that underlie retinoblastoma. Eighty-three enucleated retinoblastoma specimens were evaluated using a MSK-IMPACT clinical next-generation sequencing panel to evaluate both somatic and germline alterations. Somatic copy number variations (CNVs) were also identified. Genetic profiles were correlated to clinicopathologic characteristics. RB1 inactivation was found in 79 (97.5%) patients. All specimens had additional molecular alterations. The most common non-RB1 gene alteration was BCOR in 19 (22.9%). Five (11.0%) had pathogenic germline mutations in other non-RB1 cancer predisposition genes. Significant clinicopathologic correlations included: vitreous seeds associated with 1q gains and 16q loss of heterozygosity (BH-corrected p-value = 0.008, 0.004; OR = 12.6, 26.7, respectively). BCOR mutations were associated with poor prognosis, specifically metastases-free survival (MFS) (nominal p-value 0.03). Furthermore, retinoblastoma patients can have non-RB1 germline mutations in other cancer-associated genes. No two specimens had the identical genetic profile, emphasizing the individuality of tumors with the same clinical diagnosis.

Highlights

Retinoblastoma is the most common primary pediatric intraocular tumor [1]
Loss of heterozygosity, and homozygous deletions leading to biallelic inactivation of RB1, we identified large-scale copy number variations (CNVs) and somatic and germline mutations in other genes not on chromosome 13
The majority of series investigating next-generation sequencing (NGS) in retinoblastoma have used this technology for germline RB1 detection, and copy number alteration details are not consistently available [18]

Summary

Introduction

Retinoblastoma is the most common primary pediatric intraocular tumor [1]. More than 100 years ago, a common genetic basis for many retinoblastomas was uncovered.While the pattern of inheritance was found to be a classical autosomal dominant pattern, it was not until the 1970s that it was recognized to be caused by a loss of function of a gene, RB1. Retinoblastoma is the most common primary pediatric intraocular tumor [1]. More than 100 years ago, a common genetic basis for many retinoblastomas was uncovered. While the pattern of inheritance was found to be a classical autosomal dominant pattern, it was not until the 1970s that it was recognized to be caused by a loss of function of a gene, RB1. RB1 was the first tumor suppressor gene to be cloned (in 1986). The knowledge of RB1 alterations has been used as a part of genetic counseling for patients and families, with commercial germline RB1 testing available worldwide. Tumors are initiated by biallelic loss of the RB1 gene, with 90% penetrance [2]. Patients can present with bilateral disease derived from germline RB1 mutations or with unilateral disease, which commonly have somatic mutations but can be germline in approximately

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