Expression of the colony-stimulating factor 1 (CSF1) gene is elevated in most tenosynovial giant-cell tumors. This observation has led to the discovery and clinical development of therapy targeting the CSF1 receptor (CSF1R).

Soft tissue sarcomas (STSs) are rare, heterogeneous malignancies of connective tissues that arise from mesenchymal precursors most often in the extremities and comprise about 1% of cancers in adults.^1,2 The most common of the more than 50 biologically distinct histologies identified are leiomyosarcoma (LMS), liposarcoma (LPS), and undifferentiated pleomorphic sarcoma (UPS).^1,2 Standard first-line systemic therapy for advanced disease includes doxorubicin alone or in combination. Recent first-line phase 3 trials comparing doxorubicin monotherapy with gemcitabine plus docetaxel³ or doxorubicin plus ifosfamide,⁴ palifosfamide,⁵ or evofosfamide⁶ did not improve historic median overall survival of about 14 to 19 months and 2-year survival rates of 20% to 30%. Consequently, there is a need for new, effective treatments.

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 andTP53, receptor tyrosine kinases/PI3K/RAS, and epigenetic regulators. Subtype-specific associations includeTERTamplification 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.