TY - JOUR AU - Schieffer, Kathleen M. AU - Feldman, Alexander Z. AU - Kautto, Esko A. AU - McGrath, Sean AU - Miller, Anthony R. AU - Hernandez-Gonzalez, Maria Elena AU - LaHaye, Stephanie AU - Miller, Katherine E. AU - Koboldt, Daniel C. AU - Brennan, Patrick AU - Kelly, Benjamin AU - Wetzel, Amy AU - Agarwal, Vibhuti AU - Shatara, Margaret AU - Conley, Suzanne AU - Rodriguez, Diana P. AU - Abu-Arja, Rolla AU - Shaikhkhalil, Ala AU - Snuderl, Matija AU - Orr, Brent A. AU - Finlay, Jonathan L. AU - Osorio, Diana S. AU - Drapeau, Annie I. AU - Leonard, Jeffrey R. AU - Pierson, Christopher R. AU - White, Peter AU - Magrini, Vincent AU - Mardis, Elaine R. AU - Wilson, Richard K. AU - Cottrell, Catherine E. AU - Boué, Daniel R. PY - 2021 DA - 2021/04/07 TI - Molecular classification of a complex structural rearrangement of the RB1 locus in an infant with sporadic, isolated, intracranial, sellar region retinoblastoma JO - Acta Neuropathologica Communications SP - 61 VL - 9 IS - 1 AB - 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. SN - 2051-5960 UR - https://doi.org/10.1186/s40478-021-01164-z DO - 10.1186/s40478-021-01164-z ID - Schieffer2021 ER -