Multi-site desmoplastic small round cell tumors are genetically related and immune-cold.
Journal
NPJ precision oncology
ISSN: 2397-768X
Titre abrégé: NPJ Precis Oncol
Pays: England
ID NLM: 101708166
Informations de publication
Date de publication:
04 Apr 2022
04 Apr 2022
Historique:
received:
18
03
2021
accepted:
03
02
2022
entrez:
5
4
2022
pubmed:
6
4
2022
medline:
6
4
2022
Statut:
epublish
Résumé
Desmoplastic small round cell tumor (DSRCT) is a highly aggressive soft tissue sarcoma that is characterized by the EWSR1-WT1 fusion protein. Patients present with hundreds of tumor implants in their abdominal cavity at various sites. To determine the genetic relatedness among these sites, exome and RNA sequencing were performed on 22 DSRCT specimens from 14 patients, four of whom had specimens from various tissue sites. Multi-site tumors from individual DSRCT patients had a shared origin and were highly related. Other than the EWSR1-WT1 fusion, very few secondary cancer gene mutations were shared among the sites. Among these, ARID1A, was recurrently mutated, which corroborates findings by others in DSRCT patients. Knocking out ARID1A in JN-DSRCT cells using CRISPR/CAS9 resulted in significantly lower cell proliferation and increased drug sensitivity. The transcriptome data were integrated using network analysis and drug target database information to identify potential therapeutic opportunities in EWSR1-WT1-associated pathways, such as PI3K and mTOR pathways. Treatment of JN-DSRCT cells with the PI3K inhibitor alpelisib and mTOR inhibitor temsirolimus reduced cell proliferation. In addition, the low mutation burden was associated with an immune-cold state in DSRCT. Together, these data reveal multiple genomic and immune features of DSRCT and suggest therapeutic opportunities in patients.
Identifiants
pubmed: 35379887
doi: 10.1038/s41698-022-00257-9
pii: 10.1038/s41698-022-00257-9
pmc: PMC8980094
doi:
Types de publication
Journal Article
Langues
eng
Pagination
21Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA180279
Pays : United States
Informations de copyright
© 2022. The Author(s).
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