Clinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic targets
Benjamin A. Nacev, Francisco Sánchez-Vega, Shaleigh Smith, Cristina R. Antonescu, Evan Rosenbaum, Hongyu Shi, Cerise Tang, Nicholas D. Socci, Satshil Rana, Rodrigo Gularte‐Mérida, Ahmet Zehir, Mrinal M. Gounder, Timothy G. Bowler, Anisha Luthra, Bhumika Jadeja, Azusa Okada, Jonathan A. Strong, Jake Stoller, Jason E. Chan, Ping Chi, Sandra P. D’Angelo, Mark A. Dickson, Ciara M. Kelly, Mary Louise Keohan, Sujana Movva, Katherine A. Thornton, Paul A. Meyers, Leonard H. Wexler, Emily K. Slotkin, Julia Glade Bender, Neerav Shukla, Martee L. Hensley, John H. Healey, Michael P. LaQuaglia, Kaled M. Alektiar, Aimeé M. Crago, Sam S. Yoon, Brian R. Untch, Sarah Chiang, Narasimhan P. Agaram, Meera Hameed, Michael F. Berger, David B. Solit, Nikolaus Schultz, Marc Ladanyi, Samuel Singer, William D. Tap
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.