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Novel ATXN1/ATXN1L::NUTM2A fusions identified in aggressive infant sarcomas with gene expression and methylation patterns similar to CIC-rearranged sarcoma.

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.

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