Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma

Mrinal M. Gounder, Narasimhan P. Agaram, Sally E. Trabucco, Victoria Robinson, Richard A. Ferraro, Sherri Z. Millis, Anita Krishnan, Jessica Lee, Steven Attia, Wassim Abida, Alexander Drilon, Ping Chi, Sandra P.D’ Angelo, Mark A. Dickson, Mary Lou Keohan, Ciara M. Kelly, Mark Agulnik, Sant P. Chawla, Edwin Choy, Rashmi ChughChristian F. Meyer, Parvathi A. Myer, Jessica L. Moore, Ross A. Okimoto, Raphael E. Pollock, Vinod Ravi, Arun S. Singh, Neeta Somaiah, Andrew J. Wagner, John H. Healey, Garrett M. Frampton, Jeffrey M. Venstrom, Jeffrey S. Ross, Marc Ladanyi, Samuel Singer, Murray F. Brennan, Gary K. Schwartz, Alexander J. Lazar, David M. Thomas, Robert G. Maki, William D. Tap, Siraj M. Ali, Dexter X. Jin

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number3406
JournalNature communications
Issue number1
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)


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