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

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. (August 2010) Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat Genet, 42 (8). pp. 715-21. ISSN 1546-1718 (Electronic)1061-4036 (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/20601955
DOI: 10.1038/ng.619

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.

Item Type: Paper
Uncontrolled Keywords: Adult Aged Female Genes, Tumor Suppressor Genome Histiocytoma, Malignant Fibrous/*genetics Humans Liposarcoma/*genetics/metabolism/pathology Male Middle Aged Mutation Sarcoma/*genetics/pathology
Subjects: bioinformatics > genomics and proteomics
diseases & disorders > cancer > drugs and therapies
diseases & disorders > cancer > cancer types > sarcoma
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > tumor suppressor
CSHL Authors:
Communities: CSHL labs > Maki lab
Depositing User: Matt Covey
Date: August 2010
Date Deposited: 25 Oct 2016 15:33
Last Modified: 25 Oct 2016 15:33
PMCID: PMC2911503
Related URLs:
URI: http://repository.cshl.edu/id/eprint/33703

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