학술논문
Molecular classification of a complex structural rearrangement of the RB1 locus in an infant with sporadic, isolated, intracranial, sellar region retinoblastoma.
Document Type
Article
Author
Schieffer, Kathleen M.; Feldman, Alexander Z.; Kautto, Esko A.; McGrath, Sean; Miller, Anthony R.; Hernandez-Gonzalez, Maria Elena; LaHaye, Stephanie; Miller, Katherine E.; Koboldt, Daniel C.; Brennan, Patrick; Kelly, Benjamin; Wetzel, Amy; Agarwal, Vibhuti; Shatara, Margaret; Conley, Suzanne; Rodriguez, Diana P.; Abu-Arja, Rolla; Shaikhkhalil, Ala; Snuderl, Matija; Orr, Brent A.
Source
Subject
*INFANTS
*RETINOBLASTOMA
*RETINOBLASTOMA protein
*DNA methylation
*OCULAR tumors
*EXOMES
*OPEN reading frames (Genetics)
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Language
ISSN
2051-5960
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. [ABSTRACT FROM AUTHOR]