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Multi-platform profiling of over 2000 sarcomas: identification of biomarkers and novel therapeutic targets
Sujana Movva1, Wenhsiang Wen2, Wangjuh Chen2
1Fox Chase Cancer Center, Philadelphia, PA, USA.
Background:
Drug development in sarcoma has been hampered by the rarity and heterogeneity of the disease and lack of predictive biomarkers to therapies. We assessed protein expression and gene alterations in a large number of bone and soft tissue sarcomas in order to categorize the molecular alterations, identify predictive biomarkers and discover new therapeutic targets.
Methods:
Data from sarcoma specimens profiled for protein expression, gene amplification/translocation and DNA sequencing was reviewed.
Results:
2539 sarcoma specimens of 22 subtypes were included. TOPO2A was the most overexpressed protein at 52.8%. There was overexpression or loss of other sarcoma relevant proteins such as SPARC, PTEN and MGMT. Approximately 50% of the sarcomas expressed PD-L1 by IHC and presented with PD-1+ TILs, notably the LMS, chondrosarcomas, liposarcomas and UPS. Gene amplification/rearrangement of ALK, cMYC, HER2, PIK3CA, TOPO2A and cMET was relatively uncommon. EGFR gene amplification occurred at a rate of 16.9%. DNA sequencing of 47 genes identified mutations in 47% of the samples. The most commonly mutated genes were TP53 (26.3%) and BRCA2 (17.6%). Overexpression of TOPO2A was associated with TP53 mutation (P = 0.0001).
Conclusion:
This data provides the landscape of alterations in sarcoma. Future clinical trials are needed to validate these targets.
Insights
This study analyzed molecular alterations in over 2500 sarcoma specimens, identifying key protein and gene changes. Findings highlight potential biomarkers and therapeutic targets for sarcoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Sarcoma drug development faces challenges due to disease rarity, heterogeneity, and lack of predictive biomarkers.
- Comprehensive molecular profiling is crucial for advancing sarcoma therapies.
Purpose of the Study:
- To categorize molecular alterations in bone and soft tissue sarcomas.
- To identify predictive biomarkers for therapy response.
- To discover novel therapeutic targets for sarcoma.
Main Methods:
- Reviewed protein expression, gene amplification/translocation, and DNA sequencing data from 2539 sarcoma specimens across 22 subtypes.
- Utilized immunohistochemistry (IHC) for protein expression analysis.
- Performed DNA sequencing of 47 key genes.
Main Results:
- TOPO2A was the most overexpressed protein (52.8%), with associations to TP53 mutations.
- Approximately 50% of sarcomas expressed PD-L1 and had PD-1+ tumor-infiltrating lymphocytes (TILs).
- TP53 (26.3%) and BRCA2 (17.6%) were the most frequently mutated genes; EGFR amplification occurred in 16.9%.
Conclusions:
- This study presents a molecular landscape of sarcoma alterations.
- Identified potential biomarkers and targets warranting further investigation.
- Clinical trials are necessary to validate these findings for therapeutic application.
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