Clinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic targets

Benjamin A. Nacev, Francisco Sanchez-Vega, Shaleigh A. 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 Thornton, Paul A. Meyers, Leonard H. Wexler, Emily K. Slotkin, Julia L. Glade Bender, Neerav N. Shukla, Martee L. Hensley, John H. Healey, Michael P. Quaglia, Kaled M. Alektiar, Aimee M. Crago, Sam S. Yoon, Brian R. Untch, Sarah Chiang, Narasimhan P. Agaram, Meera R. Hameed, Michael F. Berger, David B. Solit, Nikolaus Schultz, Marc Ladanyi, Samuel Singer () and William D. Tap ()
Additional contact information
Benjamin A. Nacev: Memorial Sloan Kettering Cancer Center
Francisco Sanchez-Vega: Memorial Sloan Kettering Cancer Center
Shaleigh A. Smith: Memorial Sloan Kettering Cancer Center
Cristina R. Antonescu: Memorial Sloan Kettering Cancer Center
Evan Rosenbaum: Memorial Sloan Kettering Cancer Center
Hongyu Shi: Memorial Sloan Kettering Cancer Center
Cerise Tang: Memorial Sloan Kettering Cancer Center
Nicholas D. Socci: Memorial Sloan Kettering Cancer Center
Satshil Rana: Memorial Sloan Kettering Cancer Center
Rodrigo Gularte-Mérida: Memorial Sloan Kettering Cancer Center
Ahmet Zehir: Memorial Sloan Kettering Cancer Center
Mrinal M. Gounder: Memorial Sloan Kettering Cancer Center
Timothy G. Bowler: Memorial Sloan Kettering Cancer Center
Anisha Luthra: Memorial Sloan Kettering Cancer Center
Bhumika Jadeja: Memorial Sloan Kettering Cancer Center
Azusa Okada: Memorial Sloan Kettering Cancer Center
Jonathan A. Strong: Memorial Sloan Kettering Cancer Center
Jake Stoller: Memorial Sloan Kettering Cancer Center
Jason E. Chan: Memorial Sloan Kettering Cancer Center
Ping Chi: Memorial Sloan Kettering Cancer Center
Sandra P. D’Angelo: Memorial Sloan Kettering Cancer Center
Mark A. Dickson: Memorial Sloan Kettering Cancer Center
Ciara M. Kelly: Memorial Sloan Kettering Cancer Center
Mary Louise Keohan: Memorial Sloan Kettering Cancer Center
Sujana Movva: Memorial Sloan Kettering Cancer Center
Katherine Thornton: Memorial Sloan Kettering Cancer Center
Paul A. Meyers: Memorial Sloan Kettering Cancer Center
Leonard H. Wexler: Memorial Sloan Kettering Cancer Center
Emily K. Slotkin: Memorial Sloan Kettering Cancer Center
Julia L. Glade Bender: Memorial Sloan Kettering Cancer Center
Neerav N. Shukla: Memorial Sloan Kettering Cancer Center
Martee L. Hensley: Memorial Sloan Kettering Cancer Center
John H. Healey: Memorial Sloan Kettering Cancer Center
Michael P. Quaglia: Memorial Sloan Kettering Cancer Center
Kaled M. Alektiar: Memorial Sloan Kettering Cancer Center
Aimee M. Crago: Memorial Sloan Kettering Cancer Center
Sam S. Yoon: Memorial Sloan Kettering Cancer Center
Brian R. Untch: Memorial Sloan Kettering Cancer Center
Sarah Chiang: Memorial Sloan Kettering Cancer Center
Narasimhan P. Agaram: Memorial Sloan Kettering Cancer Center
Meera R. Hameed: Memorial Sloan Kettering Cancer Center
Michael F. Berger: Memorial Sloan Kettering Cancer Center
David B. Solit: Memorial Sloan Kettering Cancer Center
Nikolaus Schultz: Memorial Sloan Kettering Cancer Center
Marc Ladanyi: Memorial Sloan Kettering Cancer Center
Samuel Singer: Memorial Sloan Kettering Cancer Center
William D. Tap: Memorial Sloan Kettering Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30453-x

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