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

Abstract

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.