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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 States1, show remarkable histologic diversity, with more than 50 recognized subtypes2. 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.

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Figure 1: Nucleotide and copy number alterations in soft-tissue sarcoma subtypes.
Figure 2: NF1 alterations in karyotypically complex sarcomas.
Figure 3: Different effects of helical- and kinase-domain PIK3CA mutations on PI3K pathway activation and survival in MRC.
Figure 4: Genes whose knockdown is antiproliferative in dedifferentiated liposarcoma, and the consequences of CDK4, MDM2 and YEATS4 knockdown in dedifferentiated liposarcoma.

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Acknowledgements

For advice and discussion, we thank W.M. Lin, J.S. Boehm, C.M. Johannessen, A.J. Bass, M. Garber, S. Finn, J.A. Fletcher, W.C. Hahn, T. Golub and all the members of the Spanish Group for Research on Sarcomas (GEIS). We are grateful for the technical assistance and support of B.S. Blumenstail, L. Ziaugra and S.B. Gabriel of the Broad Genetic Analysis Platform; J. Baldwin of the Broad Sequencing Platform; J. Franklin, S. Mahan and K. Ardlie of the Broad Biological Samples Platform; and H. Le, P. Lizotte, B. Wong, A. Allen, A. Derr, C. Nguyen and J.K. Grenier of the Broad RNAi Platform. We thank L. Borsu for assistance with Sequenom assays at Memorial Sloan-Kettering Cancer Center (MSKCC). The MSKCC Sequenom facility is supported by the Anbinder Fund. We also thank the members of the MSKCC Genomics Core Laboratory and N.H. Moraco for clinical data support. J.A. Fletcher (Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA) and J. Nishio (Fukuoka University, Fukuoka, Japan) provided the LPS141 and FU-DDLS-1 cell lines, respectively. J.B. is a Beatriu de Pinos fellow of the Departament d'Universitats, Recerca i Societat de la Informacio de la Generalitat de Catalunya. B.S.T. is a fellow of the Geoffrey Beene Cancer Research Center at MSKCC. This work was supported in part by the Soft Tissue Sarcoma Program Project (P01 CA047179, S.J.S., M.L. and C. Sander), the Kristen Ann Carr Fund and the Starr Foundation Cancer Consortium and by a generous donation from M.B. Zuckerman.

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Contributions

The project was conceived by E.S.L., H.E.V., W.R.S., M.M. and S.S. The study was designed and overseen by J.B., B.S.T., A.L., R.G.M., L.A.G., G.K.S., E.S.L., H.E.V., W.R.S., C.R.A., M.L., C. Sander, M.M. and S.S. Sample selection and analyte processing was carried out by P.L.D., A.V., C.R.A., M.L. and S.S. Sequencing and genotyping experiments were performed by J.B., A.H.R., K.S., C.H., R.N., M.H., T. Sharpe, T.J.F., K.C., R.C.O., C. Sougnez, W.W., H.G., T. Saito, N.S. and C.L. The RNA interference screen was performed by J.B., K.S., S.J.S. and D.E.R. Validation experiments were performed by S.B., M.L.-Q., A.H. and G.K.S. Statistical and bioinformatics analyses were performed by B.S.T., A.H.R., N.D.S., B.A.W., D.Y.C., B.R., C.H.M., G.G., Y.A., R.B., S.N. and J.E.M. J.B. and B.S.T. analyzed and interpreted the results. J.B., B.S.T., S.B., A.H.R., M.L., C.S., M.M. and S.S. drafted the manuscript. All authors contributed to critical review of the paper.

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Correspondence to Chris Sander or Matthew Meyerson or Samuel Singer.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3; Supplementary Table 4 and Supplementary Note (PDF 1791 kb)

Supplementary Table 1

Clinical specimens profiled (ZIP 25 kb)

Supplementary Table 2

Genes and microRNAs sequenced and genes screened in loss-of-function RNAi experiment (ZIP 97 kb)

Supplementary Table 3

Functional impact of mutations (ZIP 11 kb)

Supplementary Table 5

DNA copy number alterations (CNAs) in soft tissue sarcoma (ZIP 51 kb)

Supplementary Table 6

Cancer proliferation genes in dedifferentiated liposarcoma (ZIP 17 kb)

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Barretina, J., Taylor, B., Banerji, S. et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat Genet 42, 715–721 (2010). https://doi.org/10.1038/ng.619

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