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Published on: August 25, 2023
Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma
Mrinal M Gounder1,2, Narasimhan P Agaram3, Sally E Trabucco4
1Memorial Sloan Kettering Cancer Center, New York, NY, USA. gounderm@mskcc.org.
Abstract:
There are more than 70 distinct sarcomas, and this diversity complicates the development of precision-based therapeutics for these cancers. Prospective comprehensive genomic profiling could overcome this challenge by providing insight into sarcomas' molecular drivers. Through targeted panel sequencing of 7494 sarcomas representing 44 histologies, we identify highly recurrent and type-specific alterations that aid in diagnosis and treatment decisions. Sequencing could lead to refinement or reassignment of 10.5% of diagnoses. Nearly one-third of patients (31.7%) harbor potentially actionable alterations, including a significant proportion (2.6%) with kinase gene rearrangements; 3.9% have a tumor mutational burden ≥10 mut/Mb. We describe low frequencies of microsatellite instability (<0.3%) and a high degree of genome-wide loss of heterozygosity (15%) across sarcomas, which are not readily explained by homologous recombination deficiency (observed in 2.5% of cases). In a clinically annotated subset of 118 patients, we validate actionable genetic events as therapeutic targets. Collectively, our findings reveal the genetic landscape of human sarcomas, which may inform future development of therapeutics and improve clinical outcomes for patients with these rare cancers.
Insights
Comprehensive genomic profiling of over 7,000 sarcomas reveals actionable genetic alterations in nearly one-third of patients. This research provides insights into the sarcoma genetic landscape to guide precision therapeutics and improve patient outcomes.
Area of Science:
- Oncology
- Genomics
- Cancer Research
Background:
- Sarcomas comprise over 70 distinct subtypes, presenting a significant challenge for developing targeted therapies.
- The molecular heterogeneity of sarcomas complicates diagnosis and treatment strategies.
Purpose of the Study:
- To investigate the genomic landscape of human sarcomas through comprehensive profiling.
- To identify recurrent and type-specific molecular alterations for improved diagnosis and treatment decisions.
- To assess the prevalence of actionable genomic alterations and their therapeutic potential in sarcomas.
Main Methods:
- Targeted panel sequencing was performed on 7494 sarcoma samples across 44 histologies.
- Genomic alterations, including gene rearrangements, tumor mutational burden, microsatellite instability, and loss of heterozygosity, were analyzed.
- Actionable genetic events were validated as therapeutic targets in a subset of 118 clinically annotated patients.
Main Results:
- Highly recurrent and histology-specific genomic alterations were identified, aiding in diagnosis and treatment.
- Sequencing data could refine or reassign diagnoses in 10.5% of cases.
- Potentially actionable alterations were found in 31.7% of patients, with kinase gene rearrangements in 2.6% and high tumor mutational burden (≥10 mut/Mb) in 3.9%.
Conclusions:
- Comprehensive genomic profiling offers a pathway to overcome sarcoma heterogeneity and guide precision medicine.
- The identified genetic landscape provides a foundation for developing novel therapeutics and improving clinical outcomes for sarcoma patients.
- Actionable genetic alterations represent promising therapeutic targets for diverse sarcoma subtypes.
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