1. Novel ATXN1/ATXN1L::NUTM2A fusions identified in aggressive infant sarcomas with gene expression and methylation patterns similar to CIC-rearranged sarcoma.
- Author
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Xu, Feng, Viaene, Angela N., Ruiz, Jenny, Schubert, Jeffrey, Wu, Jinhua, Chen, Jiani, Cao, Kajia, Fu, Weixuan, Bagatell, Rochelle, Fan, Zhiqian, Long, Ariel, Pagliaroli, Luca, Zhong, Yiming, Luo, Minjie, Kreiger, Portia A., Surrey, Lea F., Wertheim, Gerald B., Cole, Kristina A., Li, Marilyn M., and Santi, Mariarita
- Subjects
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SOFT tissue tumors , *SARCOMA , *GENE expression , *GENETIC overexpression , *INFANT diseases , *FOLLICULAR dendritic cells - Abstract
CIC-rearranged sarcomas are newly defined undifferentiated soft tissue tumors with CIC-associated fusions, and dismal prognosis. CIC fusions activate PEA3 family genes, ETV1/4/5, leading to tumorigenesis and progression. We report two high-grade CNS sarcomas of unclear histological diagnosis and one disseminated tumor of unknown origin with novel fusions and similar gene-expression/methylation patterns without CIC rearrangement. All three patients were infants with aggressive diseases, and two experienced rapid disease deterioration and death. Whole-transcriptome sequencing identified an ATXN1-NUTM2A fusion in the two CNS tumors and an ATXN1L-NUTM2A fusion in case 3. 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. 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 PEA3 family gene overexpression. These three cases with novel ATXN1/ATXN1L-associated fusions and features of CIC-rearranged sarcomas may further expand the scope of "CIC-rearranged" sarcomas to include non-CIC rearrangements. Additional cases are needed to demonstrate if ATXN1/ATXN1L-NUTM2A fusions are associated with younger age and more aggressive diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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