Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2010-08

AUTHORS

Jordi Barretina, Barry S Taylor, Shantanu Banerji, Alexis H Ramos, Mariana Lagos-Quintana, Penelope L DeCarolis, Kinjal Shah, Nicholas D Socci, Barbara A Weir, Alan Ho, Derek Y Chiang, Boris Reva, Craig H Mermel, Gad Getz, Yevgenyi Antipin, Rameen Beroukhim, John E Major, Charles Hatton, Richard Nicoletti, Megan Hanna, Ted Sharpe, Tim J Fennell, Kristian Cibulskis, Robert C Onofrio, Tsuyoshi Saito, Neerav Shukla, Christopher Lau, Sven Nelander, Serena J Silver, Carrie Sougnez, Agnes Viale, Wendy Winckler, Robert G Maki, Levi A Garraway, Alex Lash, Heidi Greulich, David E Root, William R Sellers, Gary K Schwartz, Cristina R Antonescu, Eric S Lander, Harold E Varmus, Marc Ladanyi, Chris Sander, Matthew Meyerson, Samuel Singer

ABSTRACT

Soft-tissue sarcomas, which result in approximately 10,700 diagnoses and 3,800 deaths per year in the United States, show remarkable histologic diversity, with more than 50 recognized subtypes. However, knowledge of their genomic alterations is limited. We describe an integrative analysis of DNA sequence, copy number and mRNA expression in 207 samples encompassing seven major subtypes. Frequently mutated genes included TP53 (17% of pleomorphic liposarcomas), NF1 (10.5% of myxofibrosarcomas and 8% of pleomorphic liposarcomas) and PIK3CA (18% of myxoid/round-cell liposarcomas, or MRCs). PIK3CA mutations in MRCs were associated with Akt activation and poor clinical outcomes. In myxofibrosarcomas and pleomorphic liposarcomas, we found both point mutations and genomic deletions affecting the tumor suppressor NF1. Finally, we found that short hairpin RNA (shRNA)-based knockdown of several genes amplified in dedifferentiated liposarcoma, including CDK4 and YEATS4, decreased cell proliferation. Our study yields a detailed map of molecular alterations across diverse sarcoma subtypes and suggests potential subtype-specific targets for therapy. More... »

PAGES

715

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/ng.619

DOI

http://dx.doi.org/10.1038/ng.619

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1006757412

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/20601955


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612 Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
613 The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
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615 https://www.grid.ac/institutes/grid.418424.f schema:alternateName Novartis (United States)
616 schema:name Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
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618 https://www.grid.ac/institutes/grid.51462.34 schema:alternateName Memorial Sloan Kettering Cancer Center
619 schema:name Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
620 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
621 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
622 Genomics Core Laboratory, Sloan-Kettering Institute, New York, New York, USA.
623 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
624 Laboratory of New Drug Development, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
625 Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
626 Sarcoma Biology Laboratory, Sarcoma Disease Management Program, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
627 rdf:type schema:Organization
628 https://www.grid.ac/institutes/grid.5386.8 schema:alternateName Cornell University
629 schema:name Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
630 Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, USA.
631 rdf:type schema:Organization
632 https://www.grid.ac/institutes/grid.66859.34 schema:alternateName Broad Institute
633 schema:name Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
634 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
635 The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
636 rdf:type schema:Organization
 




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