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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Jemal, A. et al. Cancer statistics, 2009. CA Cancer J. Clin. 59, 225–249 (2009).
Fletcher, C., Unni, K. & Mertens, F. (eds.) Pathology and Genetics of Tumors of Soft Tissue and Bone 427 (International Agency for Research on Cancer Press, Lyon, France, 2002).
Heinrich, M.C. et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299, 708–710 (2003).
Hirota, S. et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279, 577–580 (1998).
Demetri, G.D. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 347, 472–480 (2002).
van de Rijn, M. & Fletcher, J.A. Genetics of soft tissue tumors. Annu. Rev. Pathol. 1, 435–466 (2006).
Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069–1075 (2008).
Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).
Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).
Velculescu, V.E. Defining the blueprint of the cancer genome. Carcinogenesis 29, 1087–1091 (2008).
King, A.A., Debaun, M.R., Riccardi, V.M. & Gutmann, D.H. Malignant peripheral nerve sheath tumors in neurofibromatosis 1. Am. J. Med. Genet. 93, 388–392 (2000).
Maertens, O. et al. Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. Hum. Mol. Genet. 15, 1015–1023 (2006).
Maertens, O. et al. Comprehensive NF1 screening on cultured Schwann cells from neurofibromas. Hum. Mutat. 27, 1030–1040 (2006).
Upadhyaya, M. et al. Characterization of the somatic mutational spectrum of the neurofibromatosis type 1 (NF1) gene in neurofibromatosis patients with benign and malignant tumors. Hum. Mutat. 23, 134–146 (2004).
Singer, S. et al. Gene expression profiling of liposarcoma identifies distinct biological types/subtypes and potential therapeutic targets in well-differentiated and dedifferentiated liposarcoma. Cancer Res. 67, 6626–6636 (2007).
Antonescu, C.R. et al. Prognostic impact of P53 status, TLS-CHOP fusion transcript structure, and histological grade in myxoid liposarcoma: a molecular and clinicopathologic study of 82 cases. Clin. Cancer Res. 7, 3977–3987 (2001).
Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).
Barbareschi, M. et al. Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin. Cancer Res. 13, 6064–6069 (2007).
Huang, C.H. et al. The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 318, 1744–1748 (2007).
Miled, N. et al. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 317, 239–242 (2007).
Yuan, T.L. & Cantley, L.C. PI3K pathway alterations in cancer: variations on a theme. Oncogene 27, 5497–5510 (2008).
Beroukhim, R. et al. Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proc. Natl. Acad. Sci. USA 104, 20007–20012 (2007).
Taylor, B.S. et al. Functional copy-number alterations in cancer. PLoS One 3, e3179 (2008).
Idbaih, A. et al. Myxoid malignant fibrous histiocytoma and pleomorphic liposarcoma share very similar genomic imbalances. Lab. Invest. 85, 176–181 (2005).
König, R. et al. A probability-based approach for the analysis of large-scale RNAi screens. Nat. Methods 4, 847–849 (2007).
Luo, B. et al. Highly parallel identification of essential genes in cancer cells. Proc. Natl. Acad. Sci. USA 105, 20380–20385 (2008).
Futreal, P.A. et al. A census of human cancer genes. Nat. Rev. Cancer 4, 177–183 (2004).
Malumbres, M. & Barbacid, M. Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer 9, 153–166 (2009).
Park, J.H. & Roeder, R.G. GAS41 is required for repression of the p53 tumor suppressor pathway during normal cellular proliferation. Mol. Cell. Biol. 26, 4006–4016 (2006).
Italiano, A. et al. HMGA2 is the partner of MDM2 in well-differentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon. Int. J. Cancer 122, 2233–2241 (2008).
Müller, C.R. et al. Potential for treatment of liposarcomas with the MDM2 antagonist Nutlin-3A. Int. J. Cancer 121, 199–205 (2007).
Santarius, T., Shipley, J., Brewer, D., Stratton, M.R. & Cooper, C.S. A census of amplified and overexpressed human cancer genes. Nat. Rev. Cancer 10, 59–64 (2010).
Garcia-Echeverria, C. & Sellers, W.R. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 27, 5511–5526 (2008).
Johannessen, C.M. et al. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc. Natl. Acad. Sci. USA 102, 8573–8578 (2005).
Higgins, M.E., Claremont, M., Major, J.E., Sander, C. & Lash, A.E. CancerGenes: a gene selection resource for cancer genome projects. Nucleic Acids Res. 35, D721–D726 (2007).
Griffiths-Jones, S., Saini, H.K., van Dongen, S. & Enright, A.J. miRBase: tools for microRNA genomics. Nucleic Avids Res. 36, D154–D158 (2008).
Dutt, A. et al. Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc. Natl. Acad. Sci. USA 105, 8713–8717 (2008).
Gordon, D., Abajian, C. & Green, P. Consed: a graphical tool for sequence finishing. Genome Res. 8, 195–202 (1998).
Nickerson, D.A., Tobe, V.O. & Taylor, S.L. PolyPhred: automating the detection and genotyping of single nucleotide substitutions using fluorescence-based resequencing. Nucleic Acids Res. 25, 2745–2751 (1997).
Zhang, J. et al. SNPdetector: a software tool for sensitive and accurate SNP detection. PLOS Comput. Biol. 1, e53 (2005).
Major, J.E. Genomic mutation consequence calculator. Bioinformatics 23, 3091–3092 (2007).
Thomas, R.K. et al. High-throughput oncogene mutation profiling in human cancer. Nat. Genet. 39, 347–351 (2007).
Reva, B., Antipin, Y. & Sander, C. Determinants of protein function revealed by combinatorial entropy optimization. Genome Biol. 8, R232 (2007).
Irizarry, R.A. et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4, 249–264 (2003).
Reich, M. et al. GenePattern 2.0. Nat. Genet. 38, 500–501 (2006).
Iafrate, A.J. et al. Detection of large-scale variation in the human genome. Nat. Genet. 36, 949–951 (2004).
Lin, M. et al. dChipSNP: significance curve and clustering of SNP-array-based loss-of-heterozygosity data. Bioinformatics 20, 1233–1240 (2004).
Ambrosini, G. et al. Sorafenib inhibits growth and mitogen-activated protein kinase signaling in malignant peripheral nerve sheath cells. Mol. Cancer Ther. 7, 890–896 (2008).
Ambrosini, G. et al. Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1. Oncogene 26, 3473–3481 (2007).
Nishio, J. et al. Establishment of a novel human dedifferentiated liposarcoma cell line, FU-DDLS-1: conventional and molecular cytogenetic characterization. Int. J. Oncol. 22, 535–542 (2003).
Moffat, J. et al. A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen. Cell 124, 1283–1298 (2006).
Malo, N., Hanley, J.A., Cerquozzi, S., Pelletier, J. & Nadon, R. Statistical practice in high-throughput screening data analysis. Nat. Biotechnol. 24, 167–175 (2006).
Smyth, G.K. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat. Appl. Genet. Mol. Biol. 3, 3 (2004).
Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Statist. Soc. B 57, 289–300 (1995).
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.
The authors declare no competing financial interests.
Supplementary Figures 1–3; Supplementary Table 4 and Supplementary Note (PDF 1791 kb)
Clinical specimens profiled (ZIP 25 kb)
Genes and microRNAs sequenced and genes screened in loss-of-function RNAi experiment (ZIP 97 kb)
Functional impact of mutations (ZIP 11 kb)
DNA copy number alterations (CNAs) in soft tissue sarcoma (ZIP 51 kb)
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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