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The epigenomics of sarcoma

Nature Reviews Cancer volume 20, pages 608–623 (2020)Cite this article

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Abstract

Epigenetic regulation is critical to physiological control of development, cell fate, cell proliferation, genomic integrity and, fundamentally, transcriptional regulation. This epigenetic control occurs at multiple levels including through DNA methylation, histone modification, nucleosome remodelling and modulation of the 3D chromatin structure. Alterations in genes that encode chromatin regulators are common among mesenchymal neoplasms, a collection of more than 160 tumour types including over 60 malignant variants (sarcomas) that have unique and varied genetic, biological and clinical characteristics. Herein, we review those sarcomas in which chromatin pathway alterations drive disease biology. Specifically, we emphasize examples of dysregulation of each level of epigenetic control though mechanisms that include alterations in metabolic enzymes that regulate DNA methylation and histone post-translational modifications, mutations in histone genes, subunit loss or fusions in chromatin remodelling and modifying complexes, and disruption of higher-order chromatin structure. Epigenetic mechanisms of tumorigenesis have been implicated in mesenchymal tumours ranging from chondroblastoma and giant cell tumour of bone to chondrosarcoma, malignant peripheral nerve sheath tumour, synovial sarcoma, epithelioid sarcoma and Ewing sarcoma — all diseases that present in a younger patient population than most cancers. Finally, we review current and potential future approaches for the development of sarcoma therapies based on this emerging understanding of chromatin dysregulation.

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Fig. 1: Schematic of the five levels of epigenomics that drive transcriptional programmes in sarcomas.
Fig. 2: Classical oncohistone mutations alter histone post-translational modification ‘writer’ complex activity.
Fig. 3: Genetic alterations in histone post-translational modification ‘writer’ complex components are found in various sarcoma subtypes.
Fig. 4: Mechanisms of action of SS18–SSX in synovial sarcoma.

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References

  1. Cancer Genome Atlas Research Network. Comprehensive and integrated genomic characterization of adult soft tissue sarcomas. Cell 171, 950–965.e28 (2017). This paper presents a comprehensive genomic analysis of six major sarcoma histotypes, including MPNST and synovial sarcoma.

    Article  CAS  Google Scholar 

  2. Sheffield, N. C. et al. DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma. Nat. Med. 23, 386–395 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cancer Genome Atlas Research Network et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059–2074 (2013).

    Article  CAS  Google Scholar 

  4. Papaemmanuil, E. et al. Genomic classification and prognosis in acute myeloid leukemia. N. Engl. J. Med. 374, 2209–2221 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lohr, J. G. et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc. Natl Acad. Sci. USA 109, 3879–3884 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Okosun, J. et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat. Genet. 46, 176–181 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 68, 7–30 (2018).

    Article  PubMed  Google Scholar 

  8. National Comprehensive Cancer Network. Soft Tissue Sarcoma. NCCN https://www.nccn.org/professionals/physician_gls/PDF/sarcoma.pdf (2020).

  9. Schaefer, I.-M., Cote, G. M. & Hornick, J. L. Contemporary sarcoma diagnosis, genetics, and genomics. J. Clin. Oncol. 36, 101–110 (2018).

    Article  CAS  PubMed  Google Scholar 

  10. Jain, S., Xu, R., Prieto, V. G. & Lee, P. Molecular classification of soft tissue sarcomas and its clinical applications. Int. J. Clin. Exp. Pathol. 3, 416–428 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Barretina, J. et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat. Genet. 42, 715–721 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Vlenterie, M. et al. Next generation sequencing in synovial sarcoma reveals novel gene mutations. Oncotarget 6, 34680–34690 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Brohl, A. S. et al. The genomic landscape of the Ewing sarcoma family of tumors reveals recurrent STAG2 mutation. PLoS Genet. 10, e1004475 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Crompton, B. D. et al. The genomic landscape of pediatric Ewing sarcoma. Cancer Discov. 4, 1326–1341 (2014).

    Article  CAS  PubMed  Google Scholar 

  15. Tirode, F. et al. Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations. Cancer Discov. 4, 1342–1353 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shern, J. F. et al. Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discov. 4, 216–231 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 9, 34 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Joseph, C. G. et al. Exomic analysis of myxoid liposarcomas, synovial sarcomas, and osteosarcomas. Genes Chromosomes Cancer 53, 15–24 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. 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). This paper presents the first description of IDH1 and IDH2 mutations in chondrosarcoma.

    Article  CAS  PubMed  Google Scholar 

  20. Venneker, S., Szuhai, K., Hogendoorn, P. C. W. & Bovée, J. V. M. G. Mutation-driven epigenetic alterations as a defining hallmark of central cartilaginous tumours, giant cell tumour of bone and chondroblastoma. Virchows Arch. Path Anat. 476, 135–146 (2020).

    Article  CAS  Google Scholar 

  21. Koelsche, C. et al. Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases. Clin. Sarcoma Res. 7, 9–11 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Nacev, B. A. et al. The expanding landscape of ‘oncohistone’ mutations in human cancers. Nature 567, 473–478 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ho, P. J., Lloyd, S. M. & Bao, X. Unwinding chromatin at the right places: how BAF is targeted to specific genomic locations during development. Development 146, dev178780 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sawyer, I. A., Bartek, J. & Dundr, M. Phase separated microenvironments inside the cell nucleus are linked to disease and regulate epigenetic state, transcription and RNA processing. Semin. Cell Dev. Biol. 90, 94–103 (2019).

    Article  CAS  PubMed  Google Scholar 

  25. Wu, S. P. et al. DNA methylation-based classifier for accurate molecular diagnosis of bone sarcomas. JCO Precis. Oncol. 2017, 1–11 (2017).

    Google Scholar 

  26. Koelsche, C. et al. Array-based DNA-methylation profiling in sarcomas with small blue round cell histology provides valuable diagnostic information. Mod. Pathol. 31, 1246–1256 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Koelsche, C. et al. DNA methylation profiling distinguishes Ewing-like sarcoma with EWSR1–NFATc2 fusion from Ewing sarcoma. J. Cancer Res. Clin. Oncol. 145, 1273–1281 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Seki, M. et al. Integrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma. Nat. Commun. 6, 7557 (2015).

    Article  PubMed  Google Scholar 

  29. Röhrich, M. et al. Methylation-based classification of benign and malignant peripheral nerve sheath tumors. Acta Neuropathol. 131, 877–887 (2016).

    Article  PubMed  CAS  Google Scholar 

  30. Johann, P. D. et al. Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell 29, 379–393 (2016).

    Article  CAS  PubMed  Google Scholar 

  31. Srinivasan, U., Reaman, G. H., Poplack, D. G., Glaubiger, D. L. & LeVine, A. S. Phase II study of 5-azacytidine in sarcomas of bone. Am. J. Clin. Oncol. 5, 411–415 (1982).

    Article  CAS  PubMed  Google Scholar 

  32. Viré, E. et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439, 871–874 (2006).

    Article  PubMed  CAS  Google Scholar 

  33. Boulay, G. et al. Cancer-specific retargeting of BAF complexes by a prion-like domain. Cell 171, 163–178.e19 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chong, S. et al. Imaging dynamic and selective low-complexity domain interactions that control gene transcription. Science 361, eaar2555 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mardis, E. R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009). This study identifies IDH1 mutations as a driver event in AML.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lu, C. & Thompson, C. B. Metabolic regulation of epigenetics. Cell Metab. 16, 9–17 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Losman, J.-A. & Kaelin, W. G. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 27, 836–852 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tarpey, P. S. et al. Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma. Nat. Genet. 45, 923–926 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pansuriya, T. C. et al. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat. Genet. 43, 1256–1261 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Amary, M. F. et al. Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nat. Genet. 43, 1262–1265 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009). This paper presents the first description of the neomorphic activity of IDH1 mutations to produce the oncometabolite 2HG, mechanistically explaining its association with epigenomic dysregulation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ward, P. S. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225–234 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010). This paper shows that IDH1 and IDH2 mutations both alter DNA methylation and impair TET2 activity, leading to blocks in differentiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yen, K. et al. AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov. 7, 478–493 (2017).

    Article  CAS  PubMed  Google Scholar 

  48. Wang, F. et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340, 622–626 (2013).

    Article  CAS  PubMed  Google Scholar 

  49. Rohle, D. et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340, 626–630 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kernytsky, A. et al. IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition. Blood 125, 296–303 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. DiNardo, C. D. et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N. Engl. J. Med. 378, 2386–2398 (2018). This clinical study translates epigenomic research into new treatments, demonstrating the efficacy of IDH1 inhibitors in IDH1-mutated AML.

    Article  CAS  PubMed  Google Scholar 

  52. Stein, E. M. et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130, 722–731 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Suijker, J. et al. Inhibition of mutant IDH1 decreases d-2-HG levels without affecting tumorigenic properties of chondrosarcoma cell lines. Oncotarget 6, 12505–12519 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Jin, Y. et al. Mutant IDH1 dysregulates the differentiation of mesenchymal stem cells in association with gene-specific histone modifications to cartilage- and bone-related genes. PLoS ONE 10, e0131998 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Lu, C. et al. Induction of sarcomas by mutant IDH2. Genes Dev. 27, 1986–1998 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hirata, M. et al. Mutant IDH is sufficient to initiate enchondromatosis in mice. Proc. Natl. Acad. Sci. USA 112, 2829–2834 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sasaki, M. et al. d-2-Hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev. 26, 2038–2049 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Koivunen, P. et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483, 484–488 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Cleven, A. H. G. et al. IDH1 or -2 mutations do not predict outcome and do not cause loss of 5-hydroxymethylcytosine or altered histone modifications in central chondrosarcomas. Clin. Sarcoma Res. 7, 8–10 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Zhu, G. G. et al. Genomic profiling identifies association of IDH1/IDH2 mutation with longer relapse-free and metastasis-free survival in high-grade chondrosarcoma. Clin. Cancer Res. 26, 419–427 (2020).

    Article  CAS  PubMed  Google Scholar 

  61. Amary, M. F. et al. Isocitrate dehydrogenase 1 mutations (IDH1) and p16/CDKN2A copy number change in conventional chondrosarcomas. Virchows Arch. 466, 217–222 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Janeway, K. A. et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc. Natl Acad. Sci. USA 108, 314–318 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Pantaleo, M. A. et al. SDHA loss-of-function mutations in KIT–PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. J. Natl. Cancer Inst. 103, 983–987 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Xiao, M. et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 26, 1326–1338 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Killian, J. K. et al. Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer Discov. 3, 648–657 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Flavahan, W. A. et al. Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs. Nature 575, 229–233 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012). This paper is one of the first demonstrations of the high frequency of histone mutations in human cancers.

    Article  CAS  PubMed  Google Scholar 

  68. Wu, G. et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat. Genet. 44, 251–253 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Behjati, S. et al. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat. Genet. 45, 1479–1482 (2013). This paper demonstrates that high-frequency histone mutations occur in two distinct types of bone tumours.

    Article  CAS  PubMed  Google Scholar 

  70. Lu, C. et al. Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape. Science 352, 844–849 (2016). This study provides a mechanistic explanation of how mesenchymal tumour-associated histone mutations broadly affect the chromatin landscape and mesenchymal differentiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lewis, P. W. et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340, 857–861 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Fang, D. et al. The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas. Science 352, 1344–1348 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hübner, J.-M. et al. EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma. Neuro-Oncology 21, 878–889 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Jain, S. U. et al. PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism. Nat. Commun. 10, 2146 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Pajtler, K. W. et al. Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. Acta Neuropathol. 136, 211–226 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Piunti, A. et al. CATACOMB: an endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism. Sci. Adv. 5, eaax2887 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ragazzini, R. et al. EZHIP constrains Polycomb repressive complex 2 activity in germ cells. Nat. Commun. 10, 3858 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Fang, J. et al. Cancer-driving H3G34V/R/D mutations block H3K36 methylation and H3K36me3–MutSα interaction. Proc. Natl Acad. Sci. USA 115, 9598–9603 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Shi, L., Shi, J., Shi, X., Li, W. & Wen, H. Histone H3.3 G34 mutations alter histone H3K36 and H3K27 methylation in cis. J. Mol. Biol. 430, 1562–1565 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Zhao, S. et al. Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial–mesenchymal transition. Proc. Natl Acad. Sci. USA 113, 12238–12243 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Arimura, Y. et al. Cancer-associated mutations of histones H2B, H3.1 and H2A.Z.1 affect the structure and stability of the nucleosome. Nucleic Acids Res. 46, 10007–10018 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Boileau, M. et al. Mutant H3 histones drive human pre-leukemic hematopoietic stem cell expansion and promote leukemic aggressiveness. Nat. Commun. 10, 2891 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Bennett, R. L. et al. A mutation in histone H2B represents a new class of oncogenic driver. Cancer Discov. 9, 1438–1451 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Widemann, B. C. & Italiano, A. Biology and management of undifferentiated pleomorphic sarcoma, myxofibrosarcoma, and malignant peripheral nerve sheath tumors: state of the art and perspectives. J. Clin. Oncol. 36, 160–167 (2018).

    Article  CAS  PubMed  Google Scholar 

  85. Lee, W. et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat. Genet. 46, 1227–1232 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. De Raedt, T. et al. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature 514, 247–251 (2014). Together with Lee et al. (2014), this paper shows that loss-of-function alterations in PRC2 are common in MPNSTs.

    Article  PubMed  CAS  Google Scholar 

  87. Schuettengruber, B., Bourbon, H.-M., Di Croce, L. & Cavalli, G. Genome regulation by polycomb and trithorax: 70 years and counting. Cell 171, 34–57 (2017).

    Article  CAS  PubMed  Google Scholar 

  88. Morin, R. D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat. Genet. 42, 181–185 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Cleven, A. H. G. et al. Loss of H3K27 tri-methylation is a diagnostic marker for malignant peripheral nerve sheath tumors and an indicator for an inferior survival. Mod. Pathol. 29, 582–590 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Marchione, D. M. et al. Histone H3K27 dimethyl loss is highly specific for malignant peripheral nerve sheath tumor and distinguishes true PRC2 loss from isolated H3K27 trimethyl loss. Mod. Pathol. 32, 1434–1446 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Pierron, G. et al. A new subtype of bone sarcoma defined by BCOR–CCNB3 gene fusion. Nat. Genet. 44, 461–466 (2012). This paper is one of the first next-generation sequencing studies to identify a novel fusion oncogene driver in undifferentiated sarcomas, involving chromatin-modifying proteins.

    Article  CAS  PubMed  Google Scholar 

  92. Specht, K. et al. Novel BCOR–MAML3 and ZC3H7B–BCOR gene fusions in undifferentiated small blue round cell sarcomas. Am. J. Surg. Pathol. 40, 433–442 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Kao, Y.-C. et al. BCOR–CCNB3 fusion positive sarcomas: a clinicopathologic and molecular analysis of 36 cases with comparison to morphologic spectrum and clinical behavior of other round cell sarcomas. Am. J. Surg. Pathol. 42, 604–615 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Wang, Z. et al. A non-canonical BCOR–PRC1.1 complex represses differentiation programs in human ESCs. Cell Stem Cell 22, 235–251.e9 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Astolfi, A. et al. BCOR involvement in cancer. Epigenomics 11, 835–855 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Koontz, J. I. et al. Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors. Proc. Natl Acad. Sci. USA 98, 6348–6353 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lewis, N. et al. ZC3H7B–BCOR high-grade endometrial stromal sarcomas: a report of 17 cases of a newly defined entity. Mod. Pathol. 31, 674–684 (2018).

    Article  PubMed  Google Scholar 

  98. Panagopoulos, I. et al. Fusion of the ZC3H7B and BCOR genes in endometrial stromal sarcomas carrying an X;22-translocation. Genes Chromosomes Cancer 52, 610–618 (2013).

    Article  CAS  PubMed  Google Scholar 

  99. Ma, X. et al. The JAZF1–SUZ12 fusion protein disrupts PRC2 complexes and impairs chromatin repression during human endometrial stromal tumorogenesis. Oncotarget 8, 4062–4078 (2017).

    Article  PubMed  Google Scholar 

  100. Cao, R. et al. Role of hPHF1 in H3K27 methylation and Hox gene silencing. Mol. Cell. Biol. 28, 1862–1872 (2008).

    Article  CAS  PubMed  Google Scholar 

  101. Micci, F., Panagopoulos, I., Bjerkehagen, B. & Heim, S. Consistent rearrangement of chromosomal band 6p21 with generation of fusion genes JAZF1/PHF1 and EPC1/PHF1 in endometrial stromal sarcoma. Cancer Res. 66, 107–112 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Dewaele, B. et al. Identification of a novel, recurrent MBTD1–CXorf67 fusion in low-grade endometrial stromal sarcoma. Int. J. Cancer 134, 1112–1122 (2014).

    Article  CAS  PubMed  Google Scholar 

  103. Jacquet, K. et al. The TIP60 complex regulates bivalent chromatin recognition by 53BP1 through direct H4K20me binding and H2AK15 acetylation. Mol. Cell 62, 409–421 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Alfert, A., Moreno, N. & Kerl, K. The BAF complex in development and disease. Epigenetics Chromatin 12, 19–15 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Perani, M., Ingram, C. J. E., Cooper, C. S., Garrett, M. D. & Goodwin, G. H. Conserved SNH domain of the proto-oncoprotein SYT interacts with components of the human chromatin remodelling complexes, while the QPGY repeat domain forms homo-oligomers. Oncogene 22, 8156–8167 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Ishida, M., Tanaka, S., Ohki, M. & Ohta, T. Transcriptional co-activator activity of SYT is negatively regulated by BRM and Brg1. Genes Cells 9, 419–428 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. de Bruijn, D. R. H. et al. The synovial-sarcoma-associated SS18–SSX2 fusion protein induces epigenetic gene (de)regulation. Cancer Res. 66, 9474–9482 (2006).

    Article  PubMed  CAS  Google Scholar 

  108. Middeljans, E. et al. SS18 together with animal-specific factors defines human BAF-type SWI/SNF complexes. PLoS ONE 7, e33834 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Su, L. et al. Deconstruction of the SS18–SSX fusion oncoprotein complex: insights into disease etiology and therapeutics. Cancer Cell 21, 333–347 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Jones, K. B. et al. SS18–SSX2 and the mitochondrial apoptosis pathway in mouse and human synovial sarcomas. Oncogene 32, 2365–71–2375.e1–e5 (2013).

    Google Scholar 

  111. Garcia, C. B., Shaffer, C. M. & Eid, J. E. Genome-wide recruitment to Polycomb-modified chromatin and activity regulation of the synovial sarcoma oncogene SYT–SSX2. BMC Genomics 13, 189 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Pretto, D. et al. The synovial sarcoma translocation protein SYT–SSX2 recruits β-catenin to the nucleus and associates with it in an active complex. Oncogene 25, 3661–3669 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Kadoch, C. & Crabtree, G. R. Reversible disruption of mSWI/SNF (BAF) complexes by the SS18–SSX oncogenic fusion in synovial sarcoma. Cell 153, 71–85 (2013). This study shows that the SSX–SS18 fusion alters the composition and targeting of the SWI/SNF complex.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. McBride, M. J. et al. The SS18–SSX fusion oncoprotein hijacks BAF complex targeting and function to drive synovial sarcoma. Cancer Cell 33, 1128–1141.e7 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Wang, X. et al. SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation. Nat. Genet. 49, 289–295 (2017).

    Article  CAS  PubMed  Google Scholar 

  116. Thway, K. & Folpe, A. L. Update on selected advances in the immunohistochemical and molecular genetic analysis of soft tissue tumors. Virchows Arch. path Anat. 476, 3–15 (2020).

    Article  Google Scholar 

  117. Alpsoy, A. & Dykhuizen, E. C. Glioma tumor suppressor candidate region gene 1 (GLTSCR1) and its paralog GLTSCR1-like form SWI/SNF chromatin remodeling subcomplexes. J. Biol. Chem. 293, 3892–3903 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. McDonald, E. R. et al. Project DRIVE: a compendium of cancer dependencies and synthetic lethal relationships uncovered by large-scale, deep RNAi screening. Cell 170, 577–592.e10 (2017).

    Article  CAS  PubMed  Google Scholar 

  119. Hohmann, A. F. et al. Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition. Nat. Chem. Biol. 12, 672–679 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Krämer, K. F., Moreno, N., Frühwald, M. C. & Kerl, K. BRD9 inhibition, alone or in combination with cytostatic compounds as a therapeutic approach in rhabdoid tumors. Int. J. Mol. Sci. 18, 1537 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  121. Brien, G. L. et al. Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma. eLife 7, e41305 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Michel, B. C. et al. A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation. Nat. Cell Biol. 20, 1410–1420 (2018). Together with Brien et al. (2018), this paper identifies a dependency on BRD9 in synovial sarcoma, and proposes a role for BRD9 degradation in translational studies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Banito, A. et al. The SS18–SSX oncoprotein hijacks KDM2B–PRC1.1 to drive synovial sarcoma. Cancer Cell 33, 527–541.e8 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Pawel, B. R. SMARCB1-deficient tumors of childhood: a practical guide. Pediatr. Dev. Pathol. 21, 6–28 (2018).

    Article  PubMed  Google Scholar 

  125. Thway, K., Jones, R. L., Noujaim, J. & Fisher, C. Epithelioid sarcoma: diagnostic features and genetics. Adv. Anatomic Pathol. 23, 41–49 (2016).

    Article  CAS  Google Scholar 

  126. Guillou, L., Wadden, C., Coindre, J. M., Krausz, T. & Fletcher, C. D. ‘Proximal-type’ epithelioid sarcoma, a distinctive aggressive neoplasm showing rhabdoid features. clinicopathologic, immunohistochemical, and ultrastructural study of a series. Am. J. Surg. Pathol. 21, 130–146 (1997).

    Article  CAS  PubMed  Google Scholar 

  127. Hornick, J. L., Dal Cin, P. & Fletcher, C. D. M. Loss of INI1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma. Am. J. Surg. Pathol. 33, 542–550 (2009).

    Article  PubMed  Google Scholar 

  128. Laskin, W. B. & Miettinen, M. Epithelioid sarcoma: new insights based on an extended immunohistochemical analysis. Arch. Pathol. Lab. Med. 127, 1161–1168 (2003).

    Article  PubMed  Google Scholar 

  129. Lee, R. S. et al. A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J. Clin. Invest. 122, 2983–2988 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Jamshidi, F. et al. The genomic landscape of epithelioid sarcoma cell lines and tumours. J. Pathol. 238, 63–73 (2016).

    Article  CAS  PubMed  Google Scholar 

  131. Sullivan, L. M., Folpe, A. L., Pawel, B. R., Judkins, A. R. & Biegel, J. A. Epithelioid sarcoma is associated with a high percentage of SMARCB1 deletions. Mod. Pathol. 26, 385–392 (2013).

    Article  CAS  PubMed  Google Scholar 

  132. Papp, G., Krausz, T., Stricker, T. P., Szendrői, M. & Sápi, Z. SMARCB1 expression in epithelioid sarcoma is regulated by miR-206, miR-381, and miR-671-5p on both mRNA and protein levels. Genes Chromosomes Cancer 53, 168–176 (2014).

    Article  CAS  PubMed  Google Scholar 

  133. Sápi, Z. et al. Epigenetic regulation of SMARCB1 By miR-206, -381 and -671-5p is evident in a variety of SMARCB1 immunonegative soft tissue sarcomas, while miR-765 appears specific for epithelioid sarcoma. A miRNA study of 223 soft tissue sarcomas. Genes Chromosomes Cancer 55, 786–802 (2016).

    Article  PubMed  CAS  Google Scholar 

  134. Nakayama, R. T. et al. SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters. Nat. Genet. 49, 1613–1623 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Chun, H.-J. E. et al. Identification and analyses of extra-cranial and cranial rhabdoid tumor molecular subgroups reveal tumors with cytotoxic T cell infiltration. Cell Rep. 29, 2338–2354.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Brownlee, P. M., Meisenberg, C. & Downs, J. A. The SWI/SNF chromatin remodelling complex: its role in maintaining genome stability and preventing tumourigenesis. DNA Repair. 32, 127–133 (2015).

    Article  CAS  PubMed  Google Scholar 

  137. Peng, G. et al. BRIT1/MCPH1 links chromatin remodelling to DNA damage response. Nat. Cell Biol. 11, 865–872 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Qi, W. et al. BRG1 promotes the repair of DNA double-strand breaks by facilitating the replacement of RPA with RAD51. J. Cell. Sci. 128, 317–330 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Kakarougkas, A. et al. Requirement for PBAF in transcriptional repression and repair at DNA breaks in actively transcribed regions of chromatin. Mol. Cell 55, 723–732 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Park, J.-H. et al. Mammalian SWI/SNF complexes facilitate DNA double-strand break repair by promoting γ-H2AX induction. EMBO J. 25, 3986–3997 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02601950 (2020).

  142. Daigle, S. et al. Molecular characterization of epithelioid sarcoma (ES) tumors derived from patients enrolled in a phase II study of tazemetostat (NCT02601950) [abstract 18920]. Ann. Oncol. 29, viii670–viii682 (2018).

    Article  Google Scholar 

  143. Kohashi, K. et al. SWI/SNF chromatin-remodeling complex status in SMARCB1/INI1-preserved epithelioid sarcoma. Am. J. Surg. Pathol. 42, 312–318 (2018).

    Article  PubMed  Google Scholar 

  144. Perret, R. et al. SMARCA4-deficient thoracic sarcomas: clinicopathologic study of 30 cases with an emphasis on their nosology and differential diagnoses. Am. J. Surg. Pathol. 43, 455–465 (2019).

    Article  PubMed  Google Scholar 

  145. Rekhtman, N. et al. Thoracic SMARCA4-deficient sarcomatoid tumors represent primarily smoking-related undifferentiated carcinomas rather than primary thoracic sarcomas. J. Thorac. Oncol. 15, 231–247 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Karnezis, A. N. et al. Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type. J. Pathol. 238, 389–400 (2016).

    Article  CAS  PubMed  Google Scholar 

  147. Kolin, D. L. et al. SMARCA4-deficient undifferentiated uterine sarcoma (malignant rhabdoid tumor of the uterus): a clinicopathologic entity distinct from undifferentiated carcinoma. Mod. Pathol. 31, 1442–1456 (2018).

    Article  PubMed  Google Scholar 

  148. Lin, D. I. et al. SMARCA4 inactivation defines a subset of undifferentiated uterine sarcomas with rhabdoid and small cell features and germline mutation association. Mod. Pathol. 32, 1675–1687 (2019).

    Article  CAS  PubMed  Google Scholar 

  149. Lindén, M. et al. FET family fusion oncoproteins target the SWI/SNF chromatin remodeling complex. EMBO Rep. 20, 1741 (2019).

    Article  CAS  Google Scholar 

  150. Schwartz, J. C., Cech, T. R. & Parker, R. R. Biochemical properties and biological functions of FET proteins. Annu. Rev. Biochem. 84, 355–379 (2014).

    Article  PubMed  CAS  Google Scholar 

  151. Sankar, S. & Lessnick, S. L. Promiscuous partnerships in Ewing’s sarcoma. Cancer Genet. 204, 351–365 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Couthouis, J. et al. A yeast functional screen predicts new candidate ALS disease genes. Proc. Natl Acad. Sci. USA 108, 20881–20890 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Couthouis, J. et al. Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum. Mol. Genet. 21, 2899–2911 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Kato, M. et al. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 149, 753–767 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Kwon, I. et al. Phosphorylation-regulated binding of RNA polymerase II to fibrous polymers of low-complexity domains. Cell 155, 1049–1060 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Schwartz, J. C., Wang, X., Podell, E. R. & Cech, T. R. RNA seeds higher-order assembly of FUS protein. Cell Rep. 5, 918–925 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Burke, K. A., Janke, A. M., Rhine, C. L. & Fawzi, N. L. Residue-by-residue view of in vitro FUS granules that bind the C-terminal domain of RNA polymerase II. Mol. Cell 60, 231–241 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Patel, A. et al. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162, 1066–1077 (2015).

    CAS  PubMed  Google Scholar 

  159. Lu, H. et al. Phase-separation mechanism for C-terminal hyperphosphorylation of RNA polymerase II. Nature 558, 318–323 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Sabari, B. R. et al. Coactivator condensation at super-enhancers links phase separation and gene control. Science 361, eaar3958 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Riggi, N. et al. EWS–FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma. Cancer Cell 26, 668–681 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Boulay, G. et al. Epigenome editing of microsatellite repeats defines tumor-specific enhancer functions and dependencies. Genes Dev. 32, 1008–1019 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Tomazou, E. M. et al. Epigenome mapping reveals distinct modes of gene regulation and widespread enhancer reprogramming by the oncogenic fusion protein EWS–FLI1. Cell Rep. 10, 1082–1095 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Yoshida, K.-I. et al. Absence of H3F3A mutation in a subset of malignant giant cell tumor of bone. Mod. Pathol. 32, 1751–1761 (2019).

    Article  CAS  PubMed  Google Scholar 

  165. Chen, S. et al. Diagnostic utility of IDH1/2 mutations to distinguish dedifferentiated chondrosarcoma from undifferentiated pleomorphic sarcoma of bone. Hum. Pathol. 65, 239–246 (2017).

    Article  CAS  PubMed  Google Scholar 

  166. Noujaim, J. et al. The spectrum of EWSR1-rearranged neoplasms at a tertiary sarcoma centre; assessing 772 tumour specimens and the value of current ancillary molecular diagnostic modalities. Br. J. Cancer 116, 669–678 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Qadir, M. A. et al. ChildSeq-RNA: a next-generation sequencing-based diagnostic assay to identify known fusion transcripts in childhood sarcomas. J. Mol. Diagn. 16, 361–370 (2014).

    Article  CAS  PubMed  Google Scholar 

  168. Zhu, G. et al. Diagnosis of known sarcoma fusions and novel fusion partners by targeted RNA sequencing with identification of a recurrent ACTB–FOSB fusion in pseudomyogenic hemangioendothelioma. Mod. Pathol. 32, 609–620 (2019).

    Article  CAS  PubMed  Google Scholar 

  169. Chang, K. T. E. et al. Development and evaluation of a pan-sarcoma fusion gene detection assay using the NanoString nCounter platform. J. Mol. Diagn. 20, 63–77 (2018).

    Article  CAS  PubMed  Google Scholar 

  170. Salguero-Aranda, C., Amaral, A. T., Olmedo-Pelayo, J., Diaz-Martin, J. & Álava, E. de. Breakthrough technologies reshape the Ewing sarcoma molecular landscape. Cells 9, 804 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  171. Cermakova, K. & Hodges, H. C. Next-generation drugs and probes for chromatin biology: from targeted protein degradation to phase separation. Molecules 23, 1958 (2018).

    Article  PubMed Central  CAS  Google Scholar 

  172. Pfister, S. X. & Ashworth, A. Marked for death: targeting epigenetic changes in cancer. Nat. Rev. Drug. Discov. 16, 241–263 (2017).

    Article  CAS  PubMed  Google Scholar 

  173. Versteege, I. et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998).

    Article  CAS  PubMed  Google Scholar 

  174. Modena, P. et al. SMARCB1/INI1 tumor suppressor gene is frequently inactivated in epithelioid sarcomas. Cancer Res. 65, 4012–4019 (2005). This paper is the first report describing loss of SMARCB1 as a common event in epithelioid sarcoma.

    Article  CAS  PubMed  Google Scholar 

  175. Valencia, A. M. et al. Recurrent SMARCB1 mutations reveal a nucleosome acidic patch interaction site that potentiates mSWI/SNF complex chromatin remodeling. Cell 179, 1342–1356.e23 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Wilson, B. G. et al. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell 18, 316–328 (2010). This study demonstrates functional interactions between PRC2 and the SWI/SNF complex, with implications for epigenetic treatment strategies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Knutson, S. K. et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc. Natl Acad. Sci. USA 110, 7922–7927 (2013). This paper demonstrates that small-molecule inhibition of the catalytic subunit of PRC2 inhibits the growth of preclinical models of SWI/SNF complex-altered sarcoma, providing a scientific rationale for subsequent clinical trials with tazemetostat.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Wang, Y. et al. The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type. J. Pathol. 242, 371–383 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Stacchiotti, S. et al. Safety and efficacy of tazemetostat, a first-in-class EZH2 inhibitor, in patients (pts) with epithelioid sarcoma (ES) (NCT02601950) [abstract 11003]. JCO 37, 11003–11003 (2019).

    Article  Google Scholar 

  180. Schöffski, P. et al. Phase 2 multicenter study of the EZH2 inhibitor tazemetostat in adults with synovial sarcoma (NCT02601950) [abstract 11057]. JCO 35, 11057–11057 (2017).

    Article  Google Scholar 

  181. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02273739 (2020).

  182. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02073994 (2020).

  183. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04278781 (2020).

  184. Fan, B. et al. Clinical pharmacokinetics and pharmacodynamics of ivosidenib, an oral, targeted inhibitor of mutant IDH1, in patients with advanced solid tumors. Invest. New Drugs 462, 1–12 (2019).

    Google Scholar 

  185. Tap, W. et al. Phase I study of the mutant IDH1 inhibitor ivosidenib: safety and clinical activity in patients with advanced chondrosarcoma. J. Clin. Oncol. 38, 1693–1701 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Wang, X. et al. BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors. Nat. Commun. 10, 1881 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. McBride, M. J. & Kadoch, C. Disruption of mammalian SWI/SNF and Polycomb complexes in human sarcomas: mechanisms and therapeutic opportunities. J. Pathol. 244, 638–649 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Cooper, J. M. et al. Overcoming BET inhibitor resistance in malignant peripheral nerve sheath tumors. Clin. Cancer Res. 25, 3404–3416 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Moffat, J. G., Rudolph, J. & Bailey, D. Phenotypic screening in cancer drug discovery — past, present and future. Nat. Rev. Drug. Discov. 13, 588–602 (2014).

    Article  CAS  PubMed  Google Scholar 

  190. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

    Article  CAS  Google Scholar 

  191. Demetri, G. D. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 347, 472–480 (2002).

    Article  CAS  PubMed  Google Scholar 

  192. Doebele, R. C. et al. An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101. Cancer Discov. 5, 1049–1057 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Drilon, A. et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N. Engl. J. Med. 378, 731–739 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Laetsch, T. W. et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 19, 705–714 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02601937 (2020).

  196. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03213665 (2020).

  197. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02875548 (2020).

  198. Hyman, A. A., Weber, C. A. & Jülicher, F. Liquid–liquid phase separation in biology. Annu. Rev. Cell Dev. Biol. 30, 39–58 (2014).

    Article  CAS  PubMed  Google Scholar 

  199. Banani, S. F., Lee, H. O., Hyman, A. A. & Rosen, M. K. Biomolecular condensates: organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol. 18, 285–298 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Shin, Y. & Brangwynne, C. P. Liquid phase condensation in cell physiology and disease. Science 357, eaaf4382 (2017).

    Article  PubMed  CAS  Google Scholar 

  201. Overbeek, J. T. & Voorn, M. J. Phase separation in polyelectrolyte solutions; theory of complex coacervation. J. Cell Physiol. Suppl. 49, 7–26 (1957).

    Article  CAS  PubMed  Google Scholar 

  202. Boeynaems, S. et al. Protein phase separation: a new phase in cell biology. Trends Cell Biol. 28, 420–435 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Mao, Y. S., Zhang, B. & Spector, D. L. Biogenesis and function of nuclear bodies. Trends Genet. 27, 295–306 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Decker, C. J. & Parker, R. P-bodies and stress granules: possible roles in the control of translation and mRNA degradation. Cold Spring Harb. Perspect. Biol. 4, a012286–a012286 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  205. Li, P. et al. Phase transitions in the assembly of multivalent signalling proteins. Nature 483, 336–340 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Wang, J. et al. A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins. Cell 174, 688–699.e16 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Banjade, S. & Rosen, M. K. Phase transitions of multivalent proteins can promote clustering of membrane receptors. eLife 3, 641 (2014).

    Article  Google Scholar 

  208. Su, X. et al. Phase separation of signaling molecules promotes T cell receptor signal transduction. Science 352, 595–599 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Romero, P. et al. Sequence complexity of disordered protein. Proteins 42, 38–48 (2001).

    Article  CAS  PubMed  Google Scholar 

  210. Vucetic, S., Brown, C. J., Dunker, A. K. & Obradovic, Z. Flavors of protein disorder. Proteins 52, 573–584 (2003).

    Article  CAS  PubMed  Google Scholar 

  211. Brangwynne, C. P., Tompa, P. & Pappu, R. V. Polymer physics of intracellular phase transitions. Nat. Phys. 11, 899–904 (2015).

    Article  CAS  Google Scholar 

  212. King, O. D., Gitler, A. D. & Shorter, J. The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res. 1462, 61–80 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Boija, A. et al. Transcription factors activate genes through the phase-separation capacity of their activation domains. Cell 175, 1842–1855.e16 (2018).

    Article  CAS  PubMed  Google Scholar 

  214. Alberti, S. & Dormann, D. Liquid–liquid phase separation in disease. Annu. Rev. Genet. 53, 171–194 (2019).

    Article  CAS  PubMed  Google Scholar 

  215. Alberti, S., Gladfelter, A. & Mittag, T. Considerations and challenges in studying liquid–liquid phase separation and biomolecular condensates. Cell 176, 419–434 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. McSwiggen, D. T., Mir, M., Darzacq, X. & Tjian, R. Evaluating phase separation in live cells: diagnosis, caveats, and functional consequences. Genes Dev. 33, 1619–1634 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank P. Stirling, T. M. Underhill, M. Hirst, B. Dickson and E. Demicco for helpful discussions about some of the topics covered in this review, and A. Soshnev, M. Hirst and L. Wang for assistance in figure preparation. B.A.N is supported by the National Cancer Institute (NCI) (1K08CA245212-01) and the QuadW Foundation/American Association for Cancer Research (AACR) (19-40-37-NACE). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748, NIH/NCI P01CA196539, the Canadian Cancer Society (705615) and the Terry Fox Research Institute (1082).

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Authors and Affiliations

  1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Benjamin A. Nacev & William D. Tap

  2. The Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY, USA

    Benjamin A. Nacev & C. David Allis

  3. Department of Orthopaedics, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA

    Kevin B. Jones

  4. Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA

    Kevin B. Jones

  5. Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Andrew M. Intlekofer

  6. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    Jamie S. E. Yu & Torsten O. Nielsen

  7. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Marc Ladanyi

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Contributions

B.A.N., K.B.J., A.M.I., J.S.E.Y., W.D.T. and T.O.N. researched data for the article. B.A.N., K.B.J., A.M.I., W.D.T., M.L., C.D.A. and T.O.N. provided a substantial contribution to discussion of the content. All authors contributed to writing the article and to the review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Torsten O. Nielsen.

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Competing interests

A.M.I. previously consulted for Foundation Medicine, Inc. W.D.T. reports personal fees from Agios Pharmaceuticals, Eli Lilly, EMD Serono, Eisai, Janssen, Immune Design, Daiichi Sankyo, Blueprint, Loxo, GlaxoSmithKline, NanoCarrier and Deciphera outside the submitted work. In addition, W.D.T. has a patent Companion Diagnostic for CDK4 inhibitors (14/854,329 pending to Memorial Sloan Kettering Cancer Center (MSKCC)/Sloan Kettering Institute (SKI). W.D.T. is also on the scientific Advisory Board of Certis Oncology Solutions and Atropos Therapeutics (both stock ownership) and is a consultant for Daiichi Sankyo (FDA Oncologic Drugs Advisory Committee (ODAC) meeting, pexidartinib). T.O.N. has a patent on the Prosigna breast cancer diagnostic (Veracyte Technologies) outside the submitted work. B.A.N., K.B.J., J.S.E.Y., C.D.A. and M.L. declare no competing interests.

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Nature Reviews Cancer thanks B. Bernstein, H. Kovar and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Undifferentiated pleomorphic sarcoma

A malignant mesenchymal tumour of undefined histogenesis, with histologically characterized high-grade spindle cells producing a non-specific collagenous matrix. Previously termed malignant fibrous histiocytoma, this sarcoma is classified as a diagnosis of exclusion.

Ewing sarcoma

A malignant bone or soft tissue tumour comprising uniform small blue round cells, typically affecting children and adolescents. Driven by chromosomal translocations resulting in transcripts fusing FET genes with genes encoding ETS family transcription factors, Ewing sarcoma breakpoint region 1 (EWSR1)–friend leukaemia virus integration 1 (FLI1) being the most common variant.

Synovial sarcoma

A malignant translocation-associated sarcoma driven by the SS18–SSX gene fusion. Although frequently arising in extremities near joints, the term is a misnomer as the cell of origin is unknown and the tumour is not derived from synovium and does not differentiate into synovial-type tissue. Synovial sarcoma exists as monophasic spindle cell forms or as a biphasic type with areas of epithelial differentiation.

Gastrointestinal stromal tumours

(GISTs). Mesenchymal neoplasm of the gastrointestinal tract, derived from the interstitial cells of Cajal. Activating mutations in the KIT (or PDGFRA) receptor tyrosine kinases are the key initiating oncogenic events in the majority of cases, making imatinib and related tyrosine kinase inhibitors an effective targeted therapy for this disease.

Chondrosarcomas

Malignant cartilaginous matrix-producing tumours often driven by isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations. Typically arising in the axial skeleton of middle-aged patients, these sarcomas can be slow growing but resistant to existing systemic therapy and radiotherapy.

Nucleosomes

Basic repeating structural units of the chromosome consisting of 8 histone proteins (2 each of 4 core histones: H3, H4, H2A and H2B) with 147 base pairs of DNA wrapping the structure.

Giant cell tumour of bone

A benign but often locally aggressive neoplasm of bone in young adults driven by missense histone mutations at the histone H3.3 G34 variant. These tumours have a propensity for local recurrence and present as radiolytic lesions that destroy bone underneath articular surfaces.

Chondroblastoma

A benign cartilaginous neoplasm that characteristically arises at the ends of long bones, close to the joints, and occurs predominantly in adolescents. It is driven by the histone H3.3 K36M mutation.

Malignant peripheral nerve sheath tumours

(MPNSTs). Sarcomas arising within peripheral nerves, about half of which are sporadic and half of which occur in the context of congenital NF1 (neurofibromatosis type 1) inactivating mutations. Development of MPNSTs is additionally driven by (often mutually exclusive) loss-of-function alterations in suppressor of zeste 12 (SUZ12) or embryonic ectoderm development (EED).

Malignant rhabdoid tumours

Highly aggressive, malignant tumours that occur in infants and young children. Three presentations exist — kidney, extrarenal and brain (the latter being termed atypical teratoid/rhabdoid tumour) — and all are characterized by bi-allelic deletion of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1).

Epithelioid sarcoma

Malignant soft tissue sarcoma in distal extremities, with mixed features of mesenchymal and epithelial differentiation. It typically affects adolescents and young adults, metastasizes aggressively and is resistant to conventional chemotherapies. Epithelioid sarcoma is characterized by inactivating mutations in SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1).

Chromatin remodelling complexes

Multiple families of protein complexes that alter chromatin structure (that is, histone–DNA and histone–histone contacts) to regulate gene expression in an ATP-dependent fashion. Their functions include alteration of nucleosome assembly (maturation and spacing), chromatin access (nucleosome repositioning or ejection) and nucleosome editing (histone exchange or eviction). SWI/SNF complexes are one such family of chromatin remodelling complexes.

Enhancer

A gene regulatory element that binds transcription factors and cofactors to activate transcription of target genes that may be located a relatively far linear distance away, and independent of their orientation on DNA.

Bisulfite sequencing

The current gold-standard sequencing strategy for detecting DNA methylation based on the conversion of unmethylated cytosine to uracil after treatment with sodium bisulfite (without modification of methylated cytosine). Reduced representation bisulfite sequencing is a variation on this method that selects for areas of the genome rich in CpG islands, including promoters, with less starting material required and lower cost.

CpG islands

Segments of genomic DNA, several hundred base pairs in length, that contain a large number of CpG dinucleotide (where a cytosine is followed by a guanine) repeats. When occurring near promoters of expressed genes, CpG islands are usually unmethylated; in contrast, CpG dinucleotides occurring in other contexts tend to be methylated.

Small blue round cell sarcomas

Undifferentiated mesenchymal tumours with uniform round nuclei and very little cytoplasm that are histologically difficult to distinguish, including not only Ewing family tumours but several rarer and emerging entities with distinctive molecular drivers, prognoses and responses to therapy.

Polycomb group

(PcG). A group of proteins originally discovered in Drosophila involved in the establishment and maintenance of developmental gene expression programmes through formation of polycomb repressive complexes (PRCs) that repress gene expression by methylation of histone H3 K27 (PRC2) and ubiquitylation of H2A K119 (PRC1).

DNA hydroxymethylation

A type of DNA modification in which the oxidation of methylated cytosines at CpG dinucleotides to 5-hydroxymethylcytosine is catalysed by the TET family of methylcytosine dioxygenases. This process serves as an intermediate step in DNA demethylation.

Contact inhibition

A fundamental property of normal cells to cease proliferation or migration when in contact with neighbouring cells.

Chromatin insulator

DNA elements and protein binding partners, including CCCTC-binding factor (CTCF), that protect nearby genes from adjacent chromatin regulatory domains and can limit enhancer–promoter interactions.

Endometrial stromal sarcomas

(ESSs). Uterine malignancies with low and high-grade forms that are associated with distinct genetic rearrangements and fusion oncogenes. Typically presenting in middle age, the disease is relatively slower to progress than most other types of sarcoma.

Angiosarcoma

An aggressive, malignant endothelial cell tumour of vascular or lymphatic origin that can arise anywhere in the body, sporadically or sometimes in association with radiation exposure or lymphoedema. Angiosarcomas are especially infiltrative and prone to metastatic spread.

Desmoplastic small round cell tumour

An aggressive, malignant neoplasm and member of the small blue round cell tumour family that typically presents as a large mass in the abdomen of adolescent and young males. It is characterized by a translocation resulting in Ewing sarcoma breakpoint region 1 (EWSR1)–WT1 fusion transcripts; this sarcoma does not respond well to any currently available systemic therapies.

Homologous recombination

The exchange of nucleotide sequences between two similar or identical DNA strands that is used to generate sequence variation during meiosis or to direct error-free repair of DNA double-strand breaks.

Sarcomatoid tumours

A descriptive term for neoplasms of non-mesenchymal origin that develop a sarcoma-like histological phenotype (characterized by spindle cell cytomorphology, matrix production and cell–matrix interactions); for example, carcinomas that have undergone epithelial–mesenchymal transition.

Mediastinal tumours

A term for primary neoplasms of the thoracic cavity, other than lung cancers.

Phase separation

A physical process in which a single homogeneous liquid phase spontaneously separates into two distinct phases owing to changes in the environment, such as pH, temperature, salt or protein concentration.

Microsatellite regions

Arrays of repetitive short DNA sequences, which tend to accumulate mutations owing to the risk of strand slippage during DNA replication. These mutations are normally repaired unless there is loss of function in the mismatch repair system, which leads to microsatellite instability.

Super-enhancers

Clusters of enhancers in close genomic proximity with high concentrations of bound transcriptional co-activators that control gene expression programmes to regulate cell identity.

Chromatin looping

A model for long-range control of gene expression to allow for direct contact of promoters and enhancers over long linear distances by looping out the intervening chromatin. Loops are mediated and stabilized by proteins and complexes including CCCTC-binding factor (CTCF), mediator and cohesin.

Chromatin immunoprecipitation followed by sequencing

(ChIP–seq). A technique used to identify the DNA sequences that are in close physical proximity to a chromatin-associated protein, transcription factor or other protein of interest. In this technique, the genomic DNA is fragmented and then the protein of interest is immunoprecipitated along with associated DNA fragments, which are subsequently sequenced.

Chemical degraders

Compounds that bind a target protein through one chemical domain and through a second domain recruit the cereblon E3 ubiquitin ligase complex leading to degradation of the target protein. Degradation can have a distinct biological effect from small-molecule inhibition of the target in cases where the target protein has non-enzymatic functions.

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Nacev, B.A., Jones, K.B., Intlekofer, A.M. et al. The epigenomics of sarcoma. Nat Rev Cancer 20, 608–623 (2020). https://doi.org/10.1038/s41568-020-0288-4

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