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

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 sequenci...

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Autores principales: Gounder, Mrinal M., Agaram, Narasimhan P., Trabucco, Sally E., Robinson, Victoria, Ferraro, Richard A., Millis, Sherri Z., Krishnan, Anita, Lee, Jessica, Attia, Steven, Abida, Wassim, Drilon, Alexander, Chi, Ping, Angelo, Sandra P. D’, Dickson, Mark A., Keohan, Mary Lou, Kelly, Ciara M., Agulnik, Mark, Chawla, Sant P., Choy, Edwin, Chugh, Rashmi, Meyer, Christian F., Myer, Parvathi A., Moore, Jessica L., Okimoto, Ross A., Pollock, Raphael E., Ravi, Vinod, Singh, Arun S., Somaiah, Neeta, Wagner, Andrew J., Healey, John H., Frampton, Garrett M., Venstrom, Jeffrey M., Ross, Jeffrey S., Ladanyi, Marc, Singer, Samuel, Brennan, Murray F., Schwartz, Gary K., Lazar, Alexander J., Thomas, David M., Maki, Robert G., Tap, William D., Ali, Siraj M., Jin, Dexter X.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9200814/
https://www.ncbi.nlm.nih.gov/pubmed/35705558
http://dx.doi.org/10.1038/s41467-022-30496-0
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author Gounder, Mrinal M.
Agaram, Narasimhan P.
Trabucco, Sally E.
Robinson, Victoria
Ferraro, Richard A.
Millis, Sherri Z.
Krishnan, Anita
Lee, Jessica
Attia, Steven
Abida, Wassim
Drilon, Alexander
Chi, Ping
Angelo, Sandra P. D’
Dickson, Mark A.
Keohan, Mary Lou
Kelly, Ciara M.
Agulnik, Mark
Chawla, Sant P.
Choy, Edwin
Chugh, Rashmi
Meyer, Christian F.
Myer, Parvathi A.
Moore, Jessica L.
Okimoto, Ross A.
Pollock, Raphael E.
Ravi, Vinod
Singh, Arun S.
Somaiah, Neeta
Wagner, Andrew J.
Healey, John H.
Frampton, Garrett M.
Venstrom, Jeffrey M.
Ross, Jeffrey S.
Ladanyi, Marc
Singer, Samuel
Brennan, Murray F.
Schwartz, Gary K.
Lazar, Alexander J.
Thomas, David M.
Maki, Robert G.
Tap, William D.
Ali, Siraj M.
Jin, Dexter X.
author_facet Gounder, Mrinal M.
Agaram, Narasimhan P.
Trabucco, Sally E.
Robinson, Victoria
Ferraro, Richard A.
Millis, Sherri Z.
Krishnan, Anita
Lee, Jessica
Attia, Steven
Abida, Wassim
Drilon, Alexander
Chi, Ping
Angelo, Sandra P. D’
Dickson, Mark A.
Keohan, Mary Lou
Kelly, Ciara M.
Agulnik, Mark
Chawla, Sant P.
Choy, Edwin
Chugh, Rashmi
Meyer, Christian F.
Myer, Parvathi A.
Moore, Jessica L.
Okimoto, Ross A.
Pollock, Raphael E.
Ravi, Vinod
Singh, Arun S.
Somaiah, Neeta
Wagner, Andrew J.
Healey, John H.
Frampton, Garrett M.
Venstrom, Jeffrey M.
Ross, Jeffrey S.
Ladanyi, Marc
Singer, Samuel
Brennan, Murray F.
Schwartz, Gary K.
Lazar, Alexander J.
Thomas, David M.
Maki, Robert G.
Tap, William D.
Ali, Siraj M.
Jin, Dexter X.
author_sort Gounder, Mrinal M.
collection PubMed
description 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.
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spelling pubmed-92008142022-06-17 Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma Gounder, Mrinal M. Agaram, Narasimhan P. Trabucco, Sally E. Robinson, Victoria Ferraro, Richard A. Millis, Sherri Z. Krishnan, Anita Lee, Jessica Attia, Steven Abida, Wassim Drilon, Alexander Chi, Ping Angelo, Sandra P. D’ Dickson, Mark A. Keohan, Mary Lou Kelly, Ciara M. Agulnik, Mark Chawla, Sant P. Choy, Edwin Chugh, Rashmi Meyer, Christian F. Myer, Parvathi A. Moore, Jessica L. Okimoto, Ross A. Pollock, Raphael E. Ravi, Vinod Singh, Arun S. Somaiah, Neeta Wagner, Andrew J. Healey, John H. Frampton, Garrett M. Venstrom, Jeffrey M. Ross, Jeffrey S. Ladanyi, Marc Singer, Samuel Brennan, Murray F. Schwartz, Gary K. Lazar, Alexander J. Thomas, David M. Maki, Robert G. Tap, William D. Ali, Siraj M. Jin, Dexter X. Nat Commun Article 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. Nature Publishing Group UK 2022-06-15 /pmc/articles/PMC9200814/ /pubmed/35705558 http://dx.doi.org/10.1038/s41467-022-30496-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Gounder, Mrinal M.
Agaram, Narasimhan P.
Trabucco, Sally E.
Robinson, Victoria
Ferraro, Richard A.
Millis, Sherri Z.
Krishnan, Anita
Lee, Jessica
Attia, Steven
Abida, Wassim
Drilon, Alexander
Chi, Ping
Angelo, Sandra P. D’
Dickson, Mark A.
Keohan, Mary Lou
Kelly, Ciara M.
Agulnik, Mark
Chawla, Sant P.
Choy, Edwin
Chugh, Rashmi
Meyer, Christian F.
Myer, Parvathi A.
Moore, Jessica L.
Okimoto, Ross A.
Pollock, Raphael E.
Ravi, Vinod
Singh, Arun S.
Somaiah, Neeta
Wagner, Andrew J.
Healey, John H.
Frampton, Garrett M.
Venstrom, Jeffrey M.
Ross, Jeffrey S.
Ladanyi, Marc
Singer, Samuel
Brennan, Murray F.
Schwartz, Gary K.
Lazar, Alexander J.
Thomas, David M.
Maki, Robert G.
Tap, William D.
Ali, Siraj M.
Jin, Dexter X.
Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma
title Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma
title_full Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma
title_fullStr Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma
title_full_unstemmed Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma
title_short Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma
title_sort clinical genomic profiling in the management of patients with soft tissue and bone sarcoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9200814/
https://www.ncbi.nlm.nih.gov/pubmed/35705558
http://dx.doi.org/10.1038/s41467-022-30496-0
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