Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy Journal Article
| Authors: | Barretina, J.; Taylor, B. S.; Banerji, S.; Ramos, A. H.; Lagos-Quintana, M.; Decarolis, P. L.; Shah, K.; Socci, N. D.; Weir, B. A.; Ho, A.; Chiang, D. Y.; Reva, B.; Mermel, C. H.; Getz, G.; Antipin, Y.; Beroukhim, R.; Major, J. E.; Hatton, C.; Nicoletti, R.; Hanna, M.; Sharpe, T.; Fennell, T. J.; Cibulskis, K.; Onofrio, R. C.; Saito, T.; Shukla, N.; Lau, C.; Nelander, S.; Silver, S. J.; Sougnez, C.; Viale, A.; Winckler, W.; Maki, R. G.; Garraway, L. A.; Lash, A.; Greulich, H.; Root, D. E.; Sellers, W. R.; Schwartz, G. K.; Antonescu, C. R.; Lander, E. S.; Varmus, H. E.; Ladanyi, M.; Sander, C.; Meyerson, M.; Singer, S. |
| Article Title: | Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy |
| 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. © 2010 Nature America, Inc. All rights reserved. |
| Keywords: | protein kinase b; adolescent; adult; child; school child; aged; middle aged; unclassified drug; gene mutation; major clinical study; gene deletion; mutation; cell proliferation; gene expression; protein; protein p53; sarcoma; tumor suppressor gene; messenger rna; nucleotide sequence; soft tissue sarcoma; genomics; genome; dna sequence; leiomyosarcoma; synovial sarcoma; biological therapy; point mutation; short hairpin rna; genes, tumor suppressor; liposarcoma; cyclin dependent kinase 4; myxosarcoma; copy number variation; protein nf1; protein pik3ca; protein yeats4; fibromyxosarcoma; pleomorphic liposarcoma; round cell liposarcoma; histiocytoma, malignant fibrous |
| Journal Title: | Nature Genetics |
| Volume: | 42 |
| Issue: | 8 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2010-08-01 |
| Start Page: | 715 |
| End Page: | 721 |
| Language: | English |
| DOI: | 10.1038/ng.619 |
| PUBMED: | 20601955 |
| PROVIDER: | scopus |
| PMCID: | PMC2911503 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 10" - "Export Date: 20 April 2011" - "CODEN: NGENE" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work