Advances in sarcoma genomics and new therapeutic targets

Nature Reviews Cancer

Volumn 11, Issue 8, 2011, Pages 541-557

  Taylor, Barry S ^a,b   Barretina, Jordi ^c,d   Maki, Robert G ^e   Antonescu, Cristina R ^a   Singer, Samuel ^a   Ladanyi, Marc ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c DANA FARBER CANCER INSTITUTE   (United States)

^d BROAD INSTITUTE OF MIT AND HARVARD   (United States)

^e MOUNT SINAI SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; BEVACIZUMAB; CEDIRANIB; CHIR 265; CIXUTUMUMAB; CRIZOTINIB; DASATINIB; DENOSUMAB; ERLOTINIB; GEFITINIB; IMATINIB; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; N (2,3 DIHYDROXYPROPOXY) 3,4 DIFLUORO 2 (2 FLUORO 4 IODOANILINO)BENZAMIDE; OLARATUMAB; PANITUMUMAB; PAZOPANIB; PHOSPHOTRANSFERASE INHIBITOR; PROTEIN TYROSINE KINASE INHIBITOR; RAPAMYCIN; RECEPTOR ANTIBODY; RIDAFOROLIMUS; SCATTER FACTOR RECEPTOR INHIBITOR; SOMATOMEDIN C RECEPTOR ANTIBODY; SORAFENIB; SUNITINIB; TRABECTEDIN; TRASTUZUMAB; UNCLASSIFIED DRUG; UNINDEXED DRUG; VEMURAFENIB; VISMODEGIB;

ALVEOLAR SOFT PART SARCOMA; ANGIOMATOID FIBROUS HISTIOCYTOMA; ANGIOMYOLIPOMA; ANGIOSARCOMA; CANCER ADJUVANT THERAPY; CANCER GENETICS; CANCER PATIENT; CANCER RESISTANCE; CHONDROMA; CHONDROSARCOMA; CHORDOMA; CHRONIC MYELOID LEUKEMIA; CLEAR CELL SARCOMA; CONGENITAL FIBROSARCOMA; COPY NUMBER VARIATION; DEDIFFERENTIATED LIPOSARCOMA; DERMATOFIBROSARCOMA PROTUBERANS; DESMOID TUMOR; DESMOPLASTIC SMALL ROUND CELL TUMOR; DRUG TARGETING; ENCHONDROMA; ENDOMETRIAL STROMAL TUMOR; EWING SARCOMA; FIBROMATOSIS; FIBROMYXOID SARCOMA; GASTROINTESTINAL STROMAL TUMOR; GENE FUSION; GENOMIC INSTABILITY; GENOMICS; GIANT CELL TUMOR; HEMANGIOENDOTHELIOMA; HEMANGIOPERICYTOMA; HUMAN; LEIOMYOSARCOMA; LIPOSARCOMA; LUNG NON SMALL CELL CANCER; LYMPHANGIOLEIOMYOMATOSIS; MALIGNANT PERIPHERAL NERVE SHEATH TUMOR; MESENCHYMAL STEM CELL; MESENCHYME CHONDROSARCOMA; MYXOSARCOMA; NERVE SHEATH TUMOR; NIJMEGEN BREAKAGE SYNDROME; NONHUMAN; NUCLEAR REPROGRAMMING; NUCLEOTIDE BINDING SITE; OSTEOSARCOMA; PIGMENTED VILLONODULAR SYNOVITIS; PLASMA CELL GRANULOMA; PRIMARY TUMOR; PRIORITY JOURNAL; REVIEW; RHABDOMYOSARCOMA; ROTHMUND THOMSON SYNDROME; SARCOMA; SIGNAL TRANSDUCTION; SOLITARY FIBROUS TUMOR; SYNOVIAL SARCOMA; TRANSCRIPTION REGULATION; TREATMENT RESPONSE; TUMOR GENE; WERNER SYNDROME;

ANIMALS; ANTINEOPLASTIC AGENTS; GENOME; GENOMICS; HUMANS; MICE; MUTATION; SARCOMA; SIGNAL TRANSDUCTION;

EID: 79960847016     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc3087     Document Type: Review

References (209)

1. Fletcher, C., Unni, K. & Mertens, F. Pathology and Genetics of Tumors of Soft Tissue and Bone (International Agency for Research on Cancer Press, Lyon, 2002)
2. Jemal, A., Siegel, R., Xu, J. & Ward, E. Cancer statistics, 2010. CA Cancer J. Clin. 60, 277-300 (2010)
3. Borden, E. C. et al. Soft tissue sarcomas of adults: state of the translational science. Clin. Cancer Res. 9, 1941-1956 (2003) (Pubitemid 36687613)
4. Helman, L. J. & Meltzer, P. Mechanisms of sarcoma development. Nature Rev. Cancer 3, 685-694 (2003) (Pubitemid 37328823)
5. Mertens, F. et al. Translocation-related sarcomas. Semin. Oncol. 36, 312-323 (2009)
6. Mercado, G. E. & Barr, F. G. Fusions involving PAX and FOX genes in the molecular pathogenesis of alveolar rhabdomyosarcoma: recent advances. Curr. Mol. Med. 7, 47-61 (2007) (Pubitemid 46322278)
7. Horvai, A. E., DeVries, S., Roy, R., O'Donnell, R. J. & Waldman, F. Similarity in genetic alterations between paired well-differentiated and dedifferentiated components of dedifferentiated liposarcoma. Mod. Pathol. 22, 1477-1488 (2009)
8. Rosai, J. et al. Combined morphologic and karyotypic study of 59 atypical lipomatous tumors. Evaluation of their relationship and differential diagnosis with other adipose tissue tumors (a report of the CHAMP Study Group). Am. J. Surg. Pathol. 20, 1182-1189 (1996) (Pubitemid 26336841)
9. Snyder, E. L. et al. c-Jun amplification and overexpression are oncogenic in liposarcoma but not always sufficient to inhibit the adipocytic differentiation programme. J. Pathol. 218, 292-300 (2009)
10. Gregorian, C. et al. PTEN dosage is essential for neurofibroma development and malignant transformation. Proc. Natl Acad. Sci. USA 106, 19479-19484 (2009)
11. Subramanian, S. et al. Genome-wide transcriptome analyses reveal p53 inactivation mediated loss of miR-34a expression in malignant peripheral nerve sheath tumours. J. Pathol. 220, 58-70 (2010)
12. van Beerendonk, H. M. et al. Molecular analysis of the INK4A/INK4A-ARF gene locus in conventional (central) chondrosarcomas and enchondromas: indication of an important gene for tumour progression. J. Pathol. 202, 359-366 (2004)
13. Clark, M. A., Fisher, C., Judson, I. & Thomas, J. M. Soft-tissue sarcomas in adults. N. Engl. J. Med. 353, 701-711 (2005) (Pubitemid 41175678)
14. Mertens, F., Panagopoulos, I. & Mandahl, N. Genomic characteristics of soft tissue sarcomas. Virchows Arch. 456, 129-139 (2010)
15. Mani, R. S. & Chinnaiyan, A. M. Triggers for genomic rearrangements: insights into genomic, cellular and environmental influences. Nature Rev. Genet. 11, 819-829 (2010)
16. Novo, F. J. & Vizmanos, J. L. Chromosome translocations in cancer: computational evidence for the random generation of double-strand breaks. Trends Genet. 22, 193-196 (2006)
17. Soutoglou, E. & Misteli, T. On the contribution of spatial genome organization to cancerous chromosome translocations. J. Natl Cancer Inst. Monogr. 2008, 16-19 (2008)
18. Hosaka, T. et al. Translin binds to the sequences adjacent to the breakpoints of the TLS and CHOP genes in liposarcomas with translocation t(12;6). Oncogene 19, 5821-5825 (2000)
19. Haffner, M. C. et al. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nature Genet. 42, 668-675 (2010)
20. Lin, C. et al. Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer. Cell 139, 1069-1083 (2009)
21. Mani, R. S. et al. Induced chromosomal proximity and gene fusions in prostate cancer. Science 326, 1230 (2009)
22. Deraedt, K., Debiec-Rychter, M. & Sciot, R. Radiation-associated synovial sarcoma of the lung following radiotherapy for pulmonary metastasis of Wilms' tumour. Histopathology 48, 473-475 (2006)
23. Egger, J. F., Coindre, J. M., Benhattar, J., Coucke, P. & Guillou, L. Radiation-associated synovial sarcoma: clinicopathologic and molecular analysis of two cases. Mod. Pathol. 15, 998-1004 (2002)
24. van de Rijn, M. et al. Radiation-associated synovial sarcoma. Hum. Pathol. 28, 1325-1328 (1997 (Pubitemid 27492839)
25. Ohali, A. et al. Different telomere maintenance mechanisms in alveolar and embryonal rhabdomyosarcoma. Genes Chromosomes Cancer 47, 965-970 (2008)
26. Ulaner, G. A. et al. Divergent patterns of telomere maintenance mechanisms among human sarcomas: sharply contrasting prevalence of the alternative lengthening of telomeres mechanism in Ewing's sarcomas and osteosarcomas. Genes Chromosomes Cancer 41, 155-162 (2004) (Pubitemid 39096741)
27. Lafferty-Whyte, K. et al. A gene expression signature classifying telomerase and ALT immortalization reveals an hTERT regulatory network and suggests a mesenchymal stem cell origin for ALT. Oncogene 28, 3765-3774 (2009)
28. Hsu, J. J. et al. Werner syndrome gene variants in human sarcomas. Mol. Carcinog. 49, 166-174 (2010)
29. Meyer, S. et al. Rhabdomyosarcoma in Nijmegen breakage syndrome: strong association with perianal primary site. Cancer Genet. Cytogenet. 154, 169-174 (2004) (Pubitemid 39345814)
30. Hicks, M. J., Roth, J. R., Kozinetz, C. A. & Wang, L. L. Clinicopathologic features of osteosarcoma in patients with Rothmund-Thomson syndrome. J. Clin. Oncol. 25, 370-375 (2007) (Pubitemid 350010636)
31. Werner, S. R., Prahalad, A. K., Yang, J. & Hock, J. M. RECQL4-deficient cells are hypersensitive to oxidative stress/damage: insights for osteosarcoma prevalence and heterogeneity in Rothmund-Thomson syndrome. Biochem. Biophys. Res. Commun. 345, 403-409 (2006)
32. Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27-40 (2011)
33. Mitelman, F., Johansson, B. & Mertens, F. The impact of translocations and gene fusions on cancer causation. Nature Rev. Cancer 7, 233-245 (2007) (Pubitemid 46480968)
34. Cao, L. et al. Genome-wide identification of PAX3-FKHR binding sites in rhabdomyosarcoma reveals candidate target genes important for development and cancer. Cancer Res. 70, 6497-6508 (2010)
35. Ayalon, D., Glaser, T. & Werner, H. Transcriptional regulation of IGF-I receptor gene expression by the PAX3-FKHR oncoprotein. Growth Horm. IGF Res. 11, 289-297 (2001) (Pubitemid 34257726)
36. Ginsberg, J. P., Davis, R. J., Bennicelli, J. L., Nauta, L. E. & Barr, F. G. Up-regulation of MET but not neural cell adhesion molecule expression by the PAX3-FKHR fusion protein in alveolar rhabdomyosarcoma. Cancer Res. 58, 3542-3546 (1998) (Pubitemid 28376547)
37. Mercado, G. E. et al. Identification of PAX3-FKHR-regulated genes differentially expressed between alveolar and embryonal rhabdomyosarcoma: focus on MYCN as a biologically relevant target. Genes Chromosomes Cancer 47, 510-520 (2008) (Pubitemid 351657186)
38. Tsuda, M. et al. TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition. Cancer Res. 67, 919-929 (2007)
39. Nagai, M., Tsuda, M., Saito, T., Lae, M. & Ladanyi, M. Functional properties of ASPL-TFE3 and identification of CYP17A1 and UPP1 as direct transcriptional targets Proc. Amer Assoc. Cancer Res. Abstr. 46, 4518 (2005)
40. Guillon, N. et al. The oncogenic EWS-FLI1 protein binds in vivo GGAA microsatellite sequences with potential transcriptional activation function. PLoS ONE 4, e4932 (2009)
41. Gangwal, K. et al. Microsatellites as EWS/FLI response elements in Ewing's sarcoma. Proc. Natl Acad. Sci. USA 105, 10149-10154 (2008)
42. Boeva, V. et al. De novo motif identification improves the accuracy of predicting transcription factor binding sites in ChIP-Seq data analysis. Nucleic Acids Res. 38, e126 (2010)
43. Kovar, H. Downstream EWS/FLI1-upstream Ewing's sarcoma. Genome Med. 2, 8 (2010)
44. Graf, T. & Enver, T. Forcing cells to change lineages. Nature 462, 587-594 (2009)
45. Yamanaka, S. & Blau, H. M. Nuclear reprogramming to a pluripotent state by three approaches. Nature 465, 704-712 (2010)
46. Lessnick, S. L., Dacwag, C. S. & Golub, T. R. The Ewing's sarcoma oncoprotein EWS/FLI induces a p53-dependent growth arrest in primary human fibroblasts. Cancer Cell 1, 393-401 (2002). (Pubitemid 41039140)
47. Hu-Lieskovan, S. et al. EWS-FLI1 fusion protein up-regulates critical genes in neural crest development and is responsible for the observed phenotype of Ewing's family of tumors. Cancer Res. 65, 4633-4644 (2005) (Pubitemid 40740799)
48. Barr, F. G. Translocations, cancer and the puzzle of specificity. Nature Genet. 19, 121-124 (1998)
49. Lin, P. P., Wang, Y. & Lozano, G. Mesenchymal stem cells and the origin of Ewing's sarcoma. Sarcoma 2011, 276463 (2011)
50. Kauer, M. et al. A molecular function map of Ewing's sarcoma. PLoS ONE 4, e5415 (2009)
51. Tirode, F. et al. Mesenchymal stem cell features of Ewing tumors. Cancer Cell 11, 421-429 (2007) (Pubitemid 46680428)
52. Torchia, E. C., Jaishankar, S. & Baker, S. J. Ewing tumor fusion proteins block the differentiation of pluripotent marrow stromal cells. Cancer Res. 63, 3464-3468 (2003) (Pubitemid 36793021)
53. Li, X., McGee-Lawrence, M. E., Decker, M. & Westendorf, J. J. The Ewing's sarcoma fusion protein, EWS-FLI, binds Runx2 and blocks osteoblast differentiation. J. Cell. Biochem. 111, 933-943 (2010)
54. Riggi, N. et al. EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells. Genes Dev. 24, 916-932 (2010)
55. Riggi, N. et al. EWS-FLI-1 expression triggers a Ewing's sarcoma initiation program in primary human mesenchymal stem cells. Cancer Res. 68, 2176-2185 (2008) (Pubitemid 351521790)
56. Richter, G. H. et al. EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation. Proc. Natl Acad. Sci. USA 106, 5324-5329 (2009)
57. Fujino, T. et al. Function of EWS-POU5F1 in sarcomagenesis and tumor cell maintenance. Am. J. Pathol. 176, 1973-1982 (2010)
58. Yamaguchi, S. et al. EWSR1 is fused to POU5F1 in a bone tumor with translocation t(6;22)(p21;q12). Genes Chromosomes Cancer 43, 217-222 (2005) (Pubitemid 40570743)
59. Antonescu, C. R. et al. EWSR1-POU5F1 fusion in soft tissue myoepithelial tumors. A molecular analysis of sixty-six cases, including soft tissue, bone, and visceral lesions, showing common involvement of the EWSR1 gene. Genes Chromosomes Cancer 49, 1114-1124 (2010)
60. Moller, E. et al. POU5F1, encoding a key regulator of stem cell pluripotency, is fused to EWSR1 in hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands. J. Pathol. 215, 78-86 (2008) (Pubitemid 351619878)
61. Naka, N. et al. Synovial sarcoma is a stem cell malignancy. Stem Cells 28, 1119-1131 (2010)
62. Haldar, M., Hancock, J. D., Coffin, C. M., Lessnick, S. L. & Capecchi, M. R. A conditional mouse model of synovial sarcoma: insights into a myogenic origin. Cancer Cell 11, 375-388 (2007) (Pubitemid 46518310)
63. Haldar, M., Hedberg, M. L., Hockin, M. F. & Capecchi, M. R. A CreER-based random induction strategy for modeling translocation-associated sarcomas in mice. Cancer Res. 69, 3657-3664 (2009)
64. Ren, Y. X. et al. Mouse mesenchymal stem cells expressing PAX-FKHR form alveolar rhabdomyosarcomas by cooperating with secondary mutations. Cancer Res. 68, 6587-6597 (2008)
65. Riggi, N. et al. Expression of the FUS-CHOP fusion protein in primary mesenchymal progenitor cells gives rise to a model of myxoid liposarcoma. Cancer Res. 66, 7016-7023 (2006) (Pubitemid 44197677)
66. Agaram, N. P. et al. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer 47, 853-859 (2008)
67. Heinrich, M. C. et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299, 708-710 (2003) (Pubitemid 36159485)
68. Hirota, S. et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279, 577-580 (1998) (Pubitemid 28067289)
69. Janeway, K. A. et al. Pediatric KIT wild-type and platelet-derived growth factor receptor α-wild-type gastrointestinal stromal tumors share KIT activation but not mechanisms of genetic progression with adult gastrointestinal stromal tumors. Cancer Res. 67, 9084-9088 (2007) (Pubitemid 47535893)
70. Pasini, B. et al. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur. J. Hum. Genet. 16, 79-88 (2008) (Pubitemid 350284184)
71. Maertens, O. et al. Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. Hum. Mol. Genet. 15, 1015-1023 (2006) (Pubitemid 43338241)
72. Mussi, C., Schildhaus, H. U., Gronchi, A., Wardelmann, E. & Hohenberger, P. Therapeutic consequences from molecular biology for gastrointestinal stromal tumor patients affected by neurofibromatosis type 1. Clin. Cancer Res. 14, 4550-4555 (2008)
73. Antonescu, C. R. et al. KDR activating mutations in human angiosarcomas are sensitive to specific kinase inhibitors. Cancer Res. 69, 7175-7179 (2009)
74. Barretina, J. et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nature Genet. 42, 715-721 (2010)
75. Ito, M. et al. Comprehensive mapping of p53 pathway alterations reveals an apparent role for both SNP309 and MDM2 amplification in sarcomagenesis. Clin. Cancer Res. 17, 416-426 (2011)
76. Perot, G. et al. Constant p53 pathway inactivation in a large series of soft tissue sarcomas with complex genetics. Am. J. Pathol. 177, 2080-2090 (2010)
77. Huang, H. Y. et al. Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion: a highly lethal subset associated with poor chemoresponse. J. Clin. Oncol. 23, 548-558 (2005)
78. Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899-905 (2010)
79. Chibon, F. et al. Validated prediction of clinical outcome in sarcomas and multiple types of cancer on the basis of a gene expression signature related to genome complexity. Nature Med. 16, 781-787 (2010)
80. El-Rifai, W., Sarlomo-Rikala, M., Andersson, L. C., Knuutila, S. & Miettinen, M. DNA sequence copy number changes in gastrointestinal stromal tumors: tumor progression and prognostic significance. Cancer Res. 60, 3899-3903 (2000) (Pubitemid 32204584)
81. Ylipaa, A. et al. Integrative genomic characterization and a genomic staging system for gastrointestinal stromal tumors. Cancer 117, 380-389 (2011)
82. Pedeutour, F. et al. Structure of the supernumerary ring and giant rod chromosomes in adipose tissue tumors. Genes Chromosomes Cancer 24, 30-41 (1999) (Pubitemid 28544460)
83. Sirvent, N. et al. Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffin-embedded tumor samples: utility in diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time PCR. Am. J. Surg. Pathol. 31, 1476-1489 (2007) (Pubitemid 47482460)
84. Muller, C. R. et al. Potential for treatment of liposarcomas with the MDM2 antagonist Nutlin-3A. Int. J. Cancer 121, 199-205 (2007) (Pubitemid 46753868)
85. 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) (Pubitemid 47105508)
86. Helias-Rodzewicz, Z., Pedeutour, F., Coindre, J. M., Terrier, P. & Aurias, A. Selective elimination of amplified CDK4 sequences correlates with spontaneous adipocytic differentiation in liposarcoma. Genes Chromosomes Cancer 48, 943-952 (2009)
87. Mayr, C., Hemann, M. T. & Bartel, D. P. Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315, 1576-1579 (2007) (Pubitemid 46449474)
88. Atiye, J. et al. Gene amplifications in osteosarcoma-CGH microarray analysis. Genes Chromosomes Cancer 42, 158-163 (2005) (Pubitemid 40094099)
89. Chibon, F. et al. ASK1 (MAP3K5) as a potential therapeutic target in malignant fibrous histiocytomas with 12q14-q15 and 6q23 amplifications. Genes Chromosomes Cancer 40, 32-37 (2004) (Pubitemid 38524616)
90. Heidenblad, M. et al. Genomic profiling of bone and soft tissue tumors with supernumerary ring chromosomes using tiling resolution bacterial artificial chromosome microarrays. Oncogene 25, 7106-7116 (2006) (Pubitemid 44722078)
91. Mariani, O. et al. JUN oncogene amplification and overexpression block adipocytic differentiation in highly aggressive sarcomas. Cancer Cell 11, 361-374 (2007) (Pubitemid 46518313)
92. Helias-Rodzewicz, Z. et al. YAP1 and VGLL3, encoding two cofactors of TEAD transcription factors, are amplified and overexpressed in a subset of soft tissue sarcomas. Genes Chromosomes Cancer 49, 1161-1171 (2010)
93. Idbaih, A. et al. Myxoid malignant fibrous histiocytoma and pleomorphic liposarcoma share very similar genomic imbalances. Lab. Invest. 85, 176-181 (2005) (Pubitemid 40208921)
94. Gibault, L. et al. New insights in sarcoma oncogenesis: a comprehensive analysis of a large series of 160 soft tissue sarcomas with complex genomics. J. Pathol. 223, 64-71 (2010)
95. Adamowicz, M. et al. Frequent amplifications and abundant expression of TRIO, NKD2, and IRX2 in soft tissue sarcomas. Genes Chromosomes Cancer 45, 829-838 (2006) (Pubitemid 44182441)
96. McDermott, K. M. et al. p16(INK4a) prevents centrosome dysfunction and genomic instability in primary cells. PLoS Biol. 4, e51 (2006)
97. Shen, W. H. et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128, 157-170 (2007) (Pubitemid 46048887)
98. Meza-Zepeda, L. A. et al. Array comparative genomic hybridization reveals distinct DNA copy number differences between gastrointestinal stromal tumors and leiomyosarcomas. Cancer Res. 66, 8984-8993 (2006) (Pubitemid 44521116)
99. Beck, A. H. et al. Discovery of molecular subtypes in leiomyosarcoma through integrative molecular profiling. Oncogene 29, 845-854 (2010)
100. Kimura, Y., Morita, T., Hayashi, K., Miki, T. & Sobue, K. Myocardin functions as an effective inducer of growth arrest and differentiation in human uterine leiomyosarcoma cells. Cancer Res. 70, 501-511 (2010)
101. Perot, G. et al. Strong smooth muscle differentiation is dependent on myocardin gene amplification in most human retroperitoneal leiomyosarcomas. Cancer Res. 69, 2269-2278 (2009)
102. Garraway, L. A. & Sellers, W. R. Lineage dependency and lineage-survival oncogenes in human cancer. Nature Rev. Cancer 6, 593-602 (2006) (Pubitemid 44140858)
103. Bignell, G. R. et al. Signatures of mutation and selection in the cancer genome. Nature 463, 893-898 (2010)
104. Sharma, S. V., Haber, D. A. & Settleman, J. Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents. Nature Rev. Cancer 10, 241-253 (2010)
105. Luo, B. et al. Highly parallel identification of essential genes in cancer cells. Proc. Natl Acad. Sci. USA 105, 20380-20385 (2008)
106. 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)
107. Johannessen, C. M. et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468, 968-972 (2010)
108. Macarulla, T. et al. Phase I study of the selective Aurora A kinase inhibitor MLN8054 in patients with advanced solid tumors: safety, pharmacokinetics, and pharmacodynamics. Mol. Cancer Ther. 9, 2844-2852 (2010)
109. Rui, L. et al. Cooperative epigenetic modulation by cancer amplicon genes. Cancer Cell 18, 590-605 (2010)
110. Vaira, V. et al. Preclinical model of organotypic culture for pharmacodynamic profiling of human tumors. Proc. Natl Acad. Sci. USA 107, 8352-8356 (2010)
111. Martinez, N. et al. Transcriptional signature of Ecteinascidin 743 (Yondelis, Trabectedin) in human sarcoma cells explanted from chemo-naive patients. Mol. Cancer Ther. 4, 814-823 (2005) (Pubitemid 40767126)
112. Peng, T. et al. An experimental model for the study of well-differentiated and dedifferentiated liposarcoma; deregulation of targetable tyrosine kinase receptors. Lab. Invest. 91, 392-403 (2011)
113. Frapolli, R. et al. Novel models of myxoid liposarcoma xenografts mimicking the biological and pharmacologic features of human tumors. Clin. Cancer Res. 16, 4958-4967 (2010)
114. Hernando, E. et al. The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas. Nature Med. 13, 748-753 (2007) (Pubitemid 46889749)
115. Kirsch, D. G. et al. A spatially and temporally restricted mouse model of soft tissue sarcoma. Nature Med. 13, 992-997 (2007) (Pubitemid 47222037)
116. Keller, C. et al. Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function. Genes Dev. 18, 2614-2626 (2004) (Pubitemid 39453101)
117. Perez-Losada, J. et al. The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas in transgenic mice. Oncogene 19, 2413-2422 (2000) (Pubitemid 30323474)
118. Sommer, G. et al. Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase. Proc. Natl Acad. Sci. USA 100, 6706-6711 (2003) (Pubitemid 36666644)
119. Rubin, B. P. et al. A knock-in mouse model of gastrointestinal stromal tumor harboring kit K641E. Cancer Res. 65, 6631-6639 (2005) (Pubitemid 41060699)
120. Zender, L. et al. An oncogenomics-based in vivo RNAi screen identifies tumor suppressors in liver cancer. Cell 135, 852-864 (2008)
121. Bric, A. et al. Functional identification of tumor-suppressor genes through an in vivo RNA interference screen in a mouse lymphoma model. Cancer Cell 16, 324-335 (2009)
122. Meacham, C. E., Ho, E. E., Dubrovsky, E., Gertler, F. B. & Hemann, M. T. In vivo RNAi screening identifies regulators of actin dynamics as key determinants of lymphoma progression. Nature Genet. 41, 1133-1137 (2009)
123. Dodd, R. D., Mito, J. K. & Kirsch, D. G. Animal models of soft-tissue sarcoma. Dis. Model Mech. 3, 557-566 (2010)
124. Schreiber, S. L. et al. Towards patient-based cancer therapeutics. Nature Biotech. 28, 904-906 (2010)
125. Pao, W. & Chmielecki, J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nature Rev. Cancer 10, 760-774 (2010)
126. Heinrich, M. C. et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J. Clin. Oncol. 21, 4342-4349 (2003) (Pubitemid 46621810)
127. Bollag, G. et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596-599 (2010)
128. Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809-819 (2010)
129. Maki, R. G. et al. Phase II study of sorafenib in patients with metastatic or recurrent sarcomas. J. Clin. Oncol. 27, 3133-3140 (2009)
130. Sleijfer, S. et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J. Clin. Oncol. 27, 3126-3132 (2009)
131. Pappo, A. et al. Activity of R1507, a monoclonal antibody to the insulin-like growth factor-1 receptor, in patients with recurrent or refractory Ewing's sarcoma family of tumors: results of a phase II SARC study. J. Clin. Oncol. Abstr. 28, 10000 (2010)
132. Maki, R. G., Awan, R. A., Dixon, R. H., Jhanwar, S. & Antonescu, C. R. Differential sensitivity to imatinib of 2 patients with metastatic sarcoma arising from dermatofibrosarcoma protuberans. Int. J. Cancer 100, 623-626 (2002) (Pubitemid 34832970)
133. McArthur, G. A. et al. Molecular and clinical analysis of locally advanced dermatofibrosarcoma protuberans treated with imatinib: Imatinib Target Exploration Consortium Study B2225. J. Clin. Oncol. 23, 866-873 (2005) (Pubitemid 46224187)
134. Davis, I. J. et al. Oncogenic MITF dysregulation in clear cell sarcoma: defining the MiT family of human cancers. Cancer Cell 9, 473-484 (2006) (Pubitemid 43832189)
135. McGill, G. G., Haq, R., Nishimura, E. K. & Fisher, D. E. c-Met expression is regulated by Mitf in the melanocyte lineage. J. Biol. Chem. 281, 10365-10373 (2006) (Pubitemid 43864575)
136. Mosse, Y. P., Wood, A. & Maris, J. M. Inhibition of ALK signaling for cancer therapy. Clin. Cancer Res. 15, 5609-5614 (2009)
137. Kolb, E. A. & Gorlick, R. Development of IGF-IR inhibitors in pediatric sarcomas. Curr. Oncol. Rep. 11, 307-313 (2009)
138. Scotlandi, K. et al. Insulin-like growth factor I receptor-mediated circuit in Ewing's sarcoma/peripheral neuroectodermal tumor: a possible therapeutic target. Cancer Res. 56, 4570-4574 (1996) (Pubitemid 26338048)
139. Tolcher, A. W. et al. Phase I, pharmacokinetic, and pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1. J. Clin. Oncol. 27, 5800-5807 (2009)
140. Kurzrock, R. et al. A phase I study of weekly R1507, a human monoclonal antibody insulin-like growth factor-I receptor antagonist, in patients with advanced solid tumors. Clin. Cancer Res. 16, 2458-2465 (2010)
141. Olmos, D. et al. Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study. Lancet Oncol. 11, 129-135 (2010)
142. Gualberto, A. et al. Pre-treatment levels of circulating free IGF-1 identify NSCLC patients who derive clinical benefit from figitumumab. Br. J. Cancer 104, 68-74 (2011)
143. Park, M. S., Ravi, V. & Araujo, D. M. Inhibiting the VEGF-VEGFR pathway in angiosarcoma, epithelioid hemangioendothelioma, and hemangiopericytoma/solitary fibrous tumor. Curr. Opin. Oncol. 22, 351-355 (2010)
144. Gardner, K., Leahy, M., Alvarez-Gutierrez, M., Judson, I. & Scurr, M. Activity of the VEGFR/KIT tyrosine kinase inhibitor cediranib (AZD2171) in alveolar soft part sarcoma. Proc.Connect. Tissue Oncol. Soc. Abstr. 34936 (2008)
145. Stacchiotti, S. et al. Response to sunitinib malate in advanced alveolar soft part sarcoma. Clin. Cancer Res. 15, 1096-1104 (2009)
146. Bissler, J. J. et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N. Engl. J. Med. 358, 140-151 (2008)
147. Taille, C., Debray, M. P. & Crestani, B. Sirolimus treatment for pulmonary lymphangioleiomyomatosis. Ann. Intern. Med. 146, 687-688 (2007) (Pubitemid 351650533)
148. Wagner, A. J. et al. Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors. J. Clin. Oncol. 28, 835-840 (2010)
149. Cichowski, K., Santiago, S., Jardim, M., Johnson, B. W. & Jacks, T. Dynamic regulation of the Ras pathway via proteolysis of the NF1 tumor suppressor. Genes Dev. 17, 449-454 (2003) (Pubitemid 36258759)
150. Johannessen, C. M. et al. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc. Natl Acad. Sci. USA 102, 8573-8578 (2005) (Pubitemid 40862777)
151. Forni, C. et al. Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors. Mol. Cancer Ther. 8, 449-457 (2009)
152. Grosso, F. et al. Trabectedin in myxoid liposarcomas (MLS): a long-term analysis of a single-institution series. Ann. Oncol. 20, 1439-1444 (2009)
153. Minuzzo, M. et al. Selective effects of the anticancer drug Yondelis (ET-743) on cell-cycle promoters. Mol. Pharmacol. 68, 1496-1503 (2005) (Pubitemid 41540005)
154. Martinez-Serra, J. et al. Yondelis® (ET-743, Trabectedin) sensitizes cancer cell lines to CD95-mediated cell death: new molecular insight into the mechanism of action. Eur. J. Pharmacol. 658, 57-64 (2011)
155. Schoffski, P. et al. Predictive impact of DNA repair functionality on clinical outcome of advanced sarcoma patients treated with trabectedin: a retrospective multicentric study. Eur. J. Cancer 47, 1006-1012 (2011)
156. Gramza, A. W., Corless, C. L. & Heinrich, M. C. Resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumors. Clin. Cancer Res. 15, 7510-7518 (2009)
157. Heinrich, M. C. et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J. Clin. Oncol. 24, 4764-4774 (2006) (Pubitemid 46630941)
158. Antonescu, C. R. et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin. Cancer Res. 11, 4182-4190 (2005) (Pubitemid 40791584)
159. Guo, T. et al. Mechanisms of sunitinib resistance in gastrointestinal stromal tumors harboring KITAY502-503ins mutation: an in vitro mutagenesis screen for drug resistance. Clin. Cancer Res. 15, 6862-6870 (2009)
160. Huang, F. et al. The mechanisms of differential sensitivity to an insulin-like growth factor-1 receptor inhibitor (BMS-536924) and rationale for combining with EGFR/HER2 inhibitors. Cancer Res. 69, 161-170 (2009)
161. Potratz, J. C. et al. Synthetic lethality screens reveal RPS6 and MST1R as modifiers of insulin-like growth factor-1 receptor inhibitor activity in childhood sarcomas. Cancer Res. 70, 8770-8781 (2010)
162. Kantarjian, H. et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 362, 2260-2270 (2010)
163. Heinrich, M. C. et al. In vitro activity of novel KIT/PDGFRA switch pocket kinase inhibitors against mutations associated with drug-resistant GI stromal tumors. J. Clin. Oncol. Abstr. 28, 10007 (2010)
164. Smith, J. R. & Workman, P. Targeting CDC37: an alternative, kinase-directed strategy for disruption of oncogenic chaperoning. Cell Cycle 8, 362-372 (2009)
165. Cutforth, T. & Rubin, G. M. Mutations in Hsp83 and cdc37 impair signaling by the sevenless receptor tyrosine kinase in Drosophila. Cell 77, 1027-1036 (1994 (Pubitemid 24208862)
166. Stepanova, L., Leng, X., Parker, S. B. & Harper, J. W. Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. Genes Dev. 10, 1491-502 (1996) (Pubitemid 26260706)
167. Knight, Z. A., Lin, H. & Shokat, K. M. Targeting the cancer kinome through polypharmacology. Nature Rev. Cancer 10, 130-137 (2010)
168. Dunker, A. K. & Uversky, V. N. Drugs for 'protein clouds': targeting intrinsically disordered transcription factors. Curr. Opin. Pharmacol. 10, 782-788 (2010)
169. Koehler, A. N. A complex task? Direct modulation of transcription factors with small molecules. Curr. Opin. Chem. Biol. 14, 331-340 (2010)
170. Erkizan, H. V. et al. A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma. Nature Med. 15, 750-756 (2009)
171. Taulli, R. et al. Validation of met as a therapeutic target in alveolar and embryonal rhabdomyosarcoma. Cancer Res. 66, 4742-4749 (2006)
172. Davis, I. J. et al. Identification of the receptor tyrosine kinase c-Met and its ligand, hepatocyte growth factor, as therapeutic targets in clear cell sarcoma. Cancer Res. 70, 639-645 (2010)
173. Ban, J. et al. EWS-FLI1 suppresses NOTCH-activated p53 in Ewing's sarcoma. Cancer Res. 68, 7100-7109 (2008)
174. Beauchamp, E. et al. GLI1 is a direct transcriptional target of EWS-FLI1 oncoprotein. J. Biol. Chem. 284, 9074-9082 (2009)
175. Zwerner, J. P. et al. The EWS/FLI1 oncogenic transcription factor deregulates GLI1. Oncogene 27, 3282-3291 (2008) (Pubitemid 351733391)
176. Navarro, D., Agra, N., Pestana, A., Alonso, J. & Gonzalez-Sancho, J. M. The EWS/FLI1 oncogenic protein inhibits expression of the Wnt inhibitor DICKKOPF-1 gene and antagonizes β-catenin/TCF-mediated transcription. Carcinogenesis 31, 394-401 (2010)
177. Hahm, K. B. Repression of the gene encoding the TGF-β type II receptor is a major target of the EWS-FLI1 oncoprotein. Nature Genet. 23, 481 (1999)
178. Im, Y. H. et al. EWS-FLI1, EWS-ERG, and EWS-ETV1 oncoproteins of Ewing tumor family all suppress transcription of transforming growth factor β type II receptor gene. Cancer Res. 60, 1536-1540 (2000)
179. Herrero-Martin, D. et al. Stable interference of EWS-FLI1 in an Ewing sarcoma cell line impairs IGF-1/IGF-1R signalling and reveals TOPK as a new target. Br. J. Cancer 101, 80-90 (2009)
180. Cironi, L. et al. IGF1 is a common target gene of Ewing's sarcoma fusion proteins in mesenchymal progenitor cells. PLoS ONE 3, e2634 (2008)
181. Prieur, A., Tirode, F., Cohen, P. & Delattre, O. EWS/FLI-1 silencing and gene profiling of Ewing cells reveal downstream oncogenic pathways and a crucial role for repression of insulin-like growth factor binding protein 3. Mol. Cell. Biol. 24, 7275-7283 (2004) (Pubitemid 39014452)
182. Maki, R. G. Small is beautiful: insulin-like growth factors and their role in growth, development, and cancer. J. Clin. Oncol. 28, 4985-4995 (2010)
183. Toretsky, J. A. & Gorlick, R. IGF-1R targeted treatment of sarcoma. Lancet Oncol. 11, 105-106 (2010)
184. Goransson, M. et al. The myxoid liposarcoma FUS-DDIT3 fusion oncoprotein deregulates NF-κB target genes by interaction with NFKBIZ. Oncogene 28, 270-278 (2009)
185. Willems, S. M. et al. Kinome profiling of myxoid liposarcoma reveals NF-κB-pathway kinase activity and casein kinase II inhibition as a potential treatment option. Mol. Cancer 9, 257 (2010)
186. Malumbres, M. & Barbacid, M. Cell cycle, CDKs and cancer: a changing paradigm. Nature Rev. Cancer 9, 153-166 (2009)
187. Ashley, E. A. et al. Clinical assessment incorporating a personal genome. Lancet 375, 1525-1535 (2010)
188. Meyerson, M., Gabriel, S. & Getz, G. Advances in understanding cancer genomes through second-generation sequencing. Nature Rev. Genet. 11, 685-696 (2010)
189. Maher, C. A. et al. Transcriptome sequencing to detect gene fusions in cancer. Nature 458, 97-101 (2009)
190. Maher, C. A. et al. Chimeric transcript discovery by paired-end transcriptome sequencing. Proc. Natl Acad. Sci. USA 106, 12353-12358 (2009)
191. Post, S. M. et al. A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development. Cancer Cell 18, 220-230 (2010)
192. 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)
193. Taylor, B. S. et al. Functional copy-number alterations in cancer. PLoS ONE 3, e3179 (2008)
194. Shen, R., Olshen, A. B. & Ladanyi, M. Integrative clustering of multiple genomic data types using a joint latent variable model with application to breast and lung cancer subtype analysis. Bioinformatics 25, 2906-2912 (2009)
195. Akavia, U. D. et al. An integrated approach to uncover drivers of cancer. Cell 143, 1005-1017 (2010)
196. Chi, P. et al. ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. Nature 467, 849-853 (2010)
197. Errani, C. et al. A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. Genes Chromosom. Cancer 50, 644-653 (2011)
198. Wang, L. et al. Identification of a novel, recurrent HEY1-NCOA2 fusion in mesenchymal chondrosarcoma based on a genome-wide screen of exon-level expression data. Genes Chromosom. Cancer (in the press)
199. Amary, M. F. et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J. Pathol. 224, 334-343 (2011)
200. Blay, J. Y., El Sayadi, H., Thiesse, P., Garret, J. & Ray-Coquard, I. Complete response to imatinib in relapsing pigmented villonodular synovitis/tenosynovial giant cell tumor (PVNS/TGCT). Ann. Oncol. 19, 821-822 (2008) (Pubitemid 351461057)
201. Antonescu, C. R. The GIST paradigm: lessons for other kinase-driven cancers. J. Pathol. 223, 251-261 (2011)
202. Skubitz, K. M., Manivel, J. C., Clohisy, D. R. & Frolich, J. W. Response of imatinib-resistant extra-abdominal aggressive fibromatosis to sunitinib: case report and review of the literature on response to tyrosine kinase inhibitors. Cancer Chemother. Pharmacol. 64, 635-640 (2009)
203. Gounder, M. et al. Activity of sorafenib against desmoid tumor/deep fibromatoses. Clin. Cancer Res. 29 Mar 2011 (doi: 10.1158/1078-0432. CCR-10-3322)
204. Thomas, D. et al. Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol. 11, 275-280 (2010)
205. Butrynski, J. E. et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N. Engl. J. Med. 363, 1727-1733 (2010)
206. Goldberg, J. et al. Preliminary results from a phase II study of ARQ 197 in patients with microphthalmia transcription factor family (MiT)-associated tumors. J. Clin. Oncol. Abstr. 27, 10502 (2009)
207. Quek, R. et al. Combination mTOR and IGF-1R inhibition: phase I trial of everolimus and figitumumab in patients with advanced sarcomas and other solid tumors. Clin. Cancer Res. 17, 871-879 (2011)
208. Stacchiotti, S. et al. Sunitinib malate and figitumumab in solitary fibrous tumor: patterns and molecular bases of tumor response. Mol. Cancer Ther. 9, 1286-1297 (2010)
209. Agulnik, M. et al. An open-label multicenter phase II study of bevacizumab for the treatment of angiosarcoma. J. Clin. Oncol. Abstr. 27, 10522 (2009)