1. Molecular classification of a complex structural rearrangement of the RB1 locus in an infant with sporadic, isolated, intracranial, sellar region retinoblastoma
- Author
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Alexander Z. Feldman, Jeffrey R. Leonard, Catherine E. Cottrell, Brent A. Orr, Peter White, Ala K. Shaikhkhalil, Amy Wetzel, Rolla Abu-Arja, Vibhuti Agarwal, Jonathan L. Finlay, Diana S Osorio, Richard K. Wilson, Annie I. Drapeau, Christopher R. Pierson, Sean McGrath, Stephanie LaHaye, Daniel C. Koboldt, Katherine E. Miller, Diana P Rodriguez, Matija Snuderl, Patrick J. Brennan, Kathleen M. Schieffer, Esko A. Kautto, Elaine R. Mardis, Maria Elena Hernandez-Gonzalez, Margaret Shatara, Vincent Magrini, Benjamin J. Kelly, Suzanne Conley, Anthony R. Miller, and Daniel R. Boue
- Subjects
Male ,Oncogene Proteins, Fusion ,Sellar-suprasellar retinoblastoma ,Ubiquitin-Protein Ligases ,DNA array-based methylation ,Case Report ,SMRT sequencing ,Biology ,DNA sequencing ,lcsh:RC346-429 ,Pathology and Forensic Medicine ,Structural variation ,Cellular and Molecular Neuroscience ,Intracranial retinoblastoma ,medicine ,Humans ,Genes, Retinoblastoma ,Exome ,lcsh:Neurology. Diseases of the nervous system ,PacBio ,Pineoblastoma ,Gene Rearrangement ,Retinoblastoma ,Brain Neoplasms ,Retinoblastoma protein ,Infant ,medicine.disease ,eye diseases ,Retinoblastoma Binding Proteins ,Cancer research ,biology.protein ,Neurology (clinical) ,DNA microarray ,RB1 ,Single molecule real time sequencing - 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.
- Published
- 2021