Novel ATXN1/ATXN1L::NUTM2A fusions identified in aggressive infant sarcomas with gene expression and methylation patterns similar to CIC-rearranged sarcoma.
ATXN1/ATXN1L-associated fusions
CIC-rearranged sarcoma
Whole transcriptome sequencing
Journal
Acta neuropathologica communications
ISSN: 2051-5960
Titre abrégé: Acta Neuropathol Commun
Pays: England
ID NLM: 101610673
Informations de publication
Date de publication:
14 07 2022
14 07 2022
Historique:
received:
24
05
2022
accepted:
22
06
2022
entrez:
14
7
2022
pubmed:
15
7
2022
medline:
19
7
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35836290
doi: 10.1186/s40478-022-01401-z
pii: 10.1186/s40478-022-01401-z
pmc: PMC9281131
doi:
Substances chimiques
ATXN1 protein, human
0
ATXN1L protein, human
0
Ataxin-1
0
Biomarkers, Tumor
0
Oncogene Proteins, Fusion
0
Repressor Proteins
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
102Subventions
Organisme : NCI NIH HHS
ID : T32 CA009679
Pays : United States
Organisme : Foundation for the National Institutes of Health
ID : U2CHL138346
Informations de copyright
© 2022. The Author(s).
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