134. Novel fusions in aggressive infant sarcomas: Expanding the scope of ‘CIC-rearranged’ sarcoma without CIC rearrangement

Aly Abdelkareem

Feng Xu

Feng Xu is a clinical genomic scientist with a focus on cancer R&D in the Division of Genomic Diagnostics at Children’s Hospital of Philadelphia (CHOP).  She has been working on several cutting-edge research and developing projects for cancer genomic diagnostic tests at CHOP. She has a rich background in genomic data analysis and a comprehensive understanding of next generation sequencing technologies from being part of the validation team for Ion Torrent PGM and extensive user experiences with Illumina and PacBio platforms.


Feng Xu, Jenny Ruiz, Jeffery Schubert, Jinhua Wu, Jiani Chen, Kajia Cao, Zhiqian Fan, Ariel Long, Yiming Zhong, Portia Kreiger, Lea Surrey, Gerald Wertheim, Kristina Cole, Mariarita Santi, Marilyn Li, Phillip Storm

Children’s Hospital of Philadelphia, Philadelphia, PA, USA

CIC-rearranged sarcomas are newly defined undifferentiated soft tissue tumors with CIC-associated fusions, mostly with DUX4, and dismal prognosis. CIC fusions activate PEA3 family genes, ETV1/4/5, leading to tumorigenesis and progression. We report three pediatric sarcomas with novel fusions and similar gene-expression/methylation patterns without CIC rearrangement.

One disseminated tumor of unknown origin and two high-grade CNS tumors of unclear histological diagnosis were received for genomic evaluation. All three patients were infants with aggressive diseases, and two experienced rapid disease deterioration and death. A series of IHC staining and comprehensive NGS panel analyses for mutations, copy number alterations, and fusions were not diagnostic. Whole-transcriptome sequencing identified an ATXN1L-NUTM2A fusion in case 1 and ATXN1-NUTM2A in the two CNS tumors. ETV1/4/5 and WT1 overexpression were observed in all three cases. Methylation analyses predicted CIC-rearranged sarcoma for all cases. Retrospective IHC staining on case 2 demonstrated ETV4 and WT1 overexpression.

An ATXN1-DUX4 fusion was recently reported in a CNS sarcoma that showed a gene expression pattern similar to that of CIC-rearranged sarcomas. ATXN1 and ATXN1L interact with CIC forming a transcription repressor complex. We propose that ATXN1/ATXN1L-associated fusions disrupt their interaction with CIC and decrease the transcription repressor complex, leading to downstream gene overexpression. These three cases, including a non-CNS tumor, with novel ATXN1/ATXN1L-associated fusions and features of CIC-rearranged sarcomas further expand the scope of ‘CIC-rearranged’ sarcomas without CIC rearrangement. Additional cases are needed to demonstrate if ATXN1/ATXN1L-NUTM2A fusions are associated with younger age and more aggressive diseases.