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Updated: Dec 28, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Clinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic
Benjamin A Nacev1,2,3, Francisco Sanchez-Vega4,5, Shaleigh A Smith4,6
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.
Abstract:
The genetic, biologic, and clinical heterogeneity of sarcomas poses a challenge for the identification of therapeutic targets, clinical research, and advancing patient care. Because there are > 100 sarcoma subtypes, in-depth genetic studies have focused on one or a few subtypes. Herein, we report a comparative genetic analysis of 2,138 sarcomas representing 45 pathological entities. This cohort is prospectively analyzed using targeted sequencing to characterize subtype-specific somatic alterations in targetable pathways, rates of whole genome doubling, mutational signatures, and subtype-agnostic genomic clusters. The most common alterations are in cell cycle control and TP53, receptor tyrosine kinases/PI3K/RAS, and epigenetic regulators. Subtype-specific associations include TERT amplification in intimal sarcoma and SWI/SNF alterations in uterine adenosarcoma. Tumor mutational burden, while low compared to other cancers, varies between and within subtypes. This resource will improve sarcoma models, motivate studies of subtype-specific alterations, and inform investigations of genetic factors and their correlations with treatment response.
Insights
This study analyzed 2,138 sarcomas, revealing common genetic alterations in cell cycle control and TP53. Findings offer insights into sarcoma heterogeneity and potential therapeutic targets for better patient care.
Area of Science:
- Oncology
- Genetics
- Genomics
Background:
- Sarcomas exhibit significant genetic, biologic, and clinical heterogeneity, complicating therapeutic target identification and patient care.
- Over 100 sarcoma subtypes exist, leading to focused genetic studies on limited entities.
- A comprehensive genetic understanding across diverse sarcoma subtypes is crucial for advancing treatment strategies.
Purpose of the Study:
- To conduct a comparative genetic analysis of a large cohort of sarcomas representing multiple pathological entities.
- To characterize subtype-specific somatic alterations, whole genome doubling rates, and mutational signatures.
- To identify subtype-agnostic genomic clusters and potential therapeutic targets within sarcomas.
Main Methods:
- Prospective targeted sequencing of 2,138 sarcomas across 45 pathological entities.
- Analysis of somatic alterations in key pathways, including cell cycle control, TP53, receptor tyrosine kinases/PI3K/RAS, and epigenetic regulators.
- Characterization of whole genome doubling rates, mutational signatures, and genomic clustering.
Main Results:
- Identified common alterations in cell cycle control, TP53, receptor tyrosine kinases/PI3K/RAS, and epigenetic regulators across sarcoma subtypes.
- Revealed subtype-specific genetic associations, such as TERT amplification in intimal sarcoma and SWI/SNF alterations in uterine adenosarcoma.
- Observed variation in tumor mutational burden between and within sarcoma subtypes.
Conclusions:
- This large-scale genetic analysis provides a valuable resource for improving sarcoma models and understanding subtype-specific alterations.
- The findings will inform future research on genetic factors influencing treatment response in sarcoma patients.
- The study highlights the potential for identifying novel therapeutic targets by dissecting sarcoma genetic heterogeneity.
