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Multi-site desmoplastic small round cell tumors are genetically related and immune-cold
Chia-Chin Wu1, Hannah C Beird1, Salah-Eddine Lamhamedi-Cherradi2
1Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
NPJ Precision Oncology
|April 5, 2022
Summary
Desmoplastic small round cell tumor (DSRCT) arises from a shared origin, with limited secondary mutations across multiple abdominal sites. Targeting ARID1A and PI3K/mTOR pathways shows therapeutic promise for this aggressive sarcoma.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive soft tissue sarcoma.
- DSRCT is characterized by the EWSR1-WT1 fusion protein and presents with widespread abdominal tumor implants.
- Understanding the genetic relatedness and molecular drivers of DSRCT is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the genetic relatedness of multi-site tumors in DSRCT patients.
- To identify secondary genetic mutations and potential therapeutic targets in DSRCT.
- To explore the immune microenvironment and its association with DSRCT characteristics.
Main Methods:
- Exome and RNA sequencing of 22 DSRCT specimens from 14 patients.
- CRISPR/CAS9 gene editing to assess the functional role of ARID1A.
- Network analysis and drug target databases to identify therapeutic opportunities.
- Analysis of mutation burden and immune cell infiltration.
Main Results:
- Multi-site tumors within individual DSRCT patients share a common origin and are highly related genetically.
- Few secondary cancer gene mutations were shared, with ARID1A being recurrently mutated.
- Knocking out ARID1A reduced cell proliferation and increased drug sensitivity in DSRCT cells.
- PI3K and mTOR pathway inhibitors (alpelisib, temsirolimus) reduced cell proliferation.
- DSRCT exhibits a low mutation burden associated with an immune-cold state.
Conclusions:
- DSRCT tumors, despite widespread dissemination, originate from a single clone.
- ARID1A is a significant secondary driver in DSRCT, and its inhibition is a potential therapeutic strategy.
- Targeting EWSR1-WT1-associated pathways like PI3K/mTOR offers therapeutic avenues.
- The immune-cold nature of DSRCT warrants further investigation for immunotherapy strategies.
