Abstract
Retinoblastoma is a childhood cancer of the retina involving germline or somatic alterations of the RB Transcriptional Corepressor 1 gene, RB1. Rare cases of sellar-suprasellar region retinoblastoma without evidence of ocular or pineal tumors have been described. A nine-month-old male presented with a sellar-suprasellar region mass. Histopathology showed an embryonal tumor with focal Flexner-Wintersteiner-like rosettes and loss of retinoblastoma protein (RB1) expression by immunohistochemistry. DNA array-based methylation profiling confidently classified the tumor as pineoblastoma group A/intracranial retinoblastoma. The patient was subsequently enrolled on an institutional translational cancer research protocol and underwent comprehensive molecular profiling, including paired tumor/normal exome and genome sequencing and RNA-sequencing of the tumor. Additionally, Pacific Biosciences (PacBio) Single Molecule Real Time (SMRT) sequencing was performed from comparator normal and disease-involved tissue to resolve complex structural variations. RNA-sequencing revealed multiple fusions clustered within 13q14.1-q21.3, including a novel in-frame fusion of RB1-SIAH3 predicted to prematurely truncate the RB1 protein. SMRT sequencing revealed a complex structural rearrangement spanning 13q14.11-q31.3, including two somatic structural variants within intron 17 of RB1. These events corresponded to the RB1-SIAH3 fusion and a novel RB1 rearrangement expected to correlate with the complete absence of RB1 protein expression. Comprehensive molecular analysis, including DNA array-based methylation profiling and sequencing-based methodologies, were critical for classification and understanding the complex mechanism of RB1 inactivation in this diagnostically challenging tumor.
Highlights
Retinoblastoma is a childhood cancer predominately occurring intraocularly, with an estimated prevalence of 1 per 16,000–18,000 live births and approximately 8,000 new cases per year [3]
Lys249*) in the absence of a germline RB Transcriptional Corepressor 1 gene (RB1) alteration, who presented with an ectopic, intracranial, sellar-suprasellar region retinoblastoma, and had a smaller similarappearing pineal mass detected on imaging [23]
DNA array-based methylation classified the tumor with high confidence as pineoblastoma group A/intracranial retinoblastoma
Summary
Retinoblastoma is a childhood cancer predominately occurring intraocularly, with an estimated prevalence of 1 per 16,000–18,000 live births and approximately 8,000 new cases per year [3]. An early case series reported an infant with isolated suprasellar tumor, without retinal involvement [13] This patient was noted to have a positive family history, including bilateral retinoblastoma in a sibling and paternal unilateral retinoblastoma. Lys249*) in the absence of a germline RB1 alteration, who presented with an ectopic, intracranial, sellar-suprasellar region retinoblastoma, and had a smaller similarappearing pineal mass detected on imaging [23]. In the latter case, the diagnosis was supported by DNA arraybased methylation profiling on the sellar region tumor; the pineal region tumor was not sampled. He tolerates full enteral calories via G-tube, has started making steady progress in improving his oral intake, and is gaining weight well
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