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The SWI/SNF complex in cancer — biology, biomarkers and therapy

Abstract

Cancer genome-sequencing studies have revealed a remarkably high prevalence of mutations in genes encoding subunits of the SWI/SNF chromatin-remodelling complexes, with nearly 25% of all cancers harbouring aberrations in one or more of these genes. A role for such aberrations in tumorigenesis is evidenced by cancer predisposition in both carriers of germline loss-of-function mutations and genetically engineered mouse models with inactivation of any of several SWI/SNF subunits. Whereas many of the most frequently mutated oncogenes and tumour-suppressor genes have been studied for several decades, the cancer-promoting role of mutations in SWI/SNF genes has been recognized only more recently, and thus comparatively less is known about these alterations. Consequently, increasing research interest is being focused on understanding the prognostic and, in particular, the potential therapeutic implications of mutations in genes encoding SWI/SNF subunits. Herein, we review the burgeoning data on the mechanisms by which mutations affecting SWI/SNF complexes promote cancer and describe promising emerging opportunities for targeted therapy, including immunotherapy with immune-checkpoint inhibitors, presented by these mutations. We also highlight ongoing clinical trials open specifically to patients with cancers harbouring mutations in certain SWI/SNF genes.

Key points

  • At least nine different genes encoding subunits of the SWI/SNF family of chromatin-remodelling complexes are recurrently mutated in cancer, and these mutations are collectively present in nearly 25% of cancers.

  • Mutations in specific SWI/SNF genes are enriched in particular cancer types, suggesting differential roles for individual SWI/SNF components; consistent with this hypothesis, different SWI/SNF gene mutations confer distinct cancer vulnerabilities in mouse models.

  • The tumour-suppressor activity of the SWI/SNF chromatin-regulatory complexes is most likely attributable to their roles in facilitating transcription factor function, which is central to cell-fate specification; however, roles of the complexes in facilitating DNA repair might also contribute.

  • The identification of potential therapeutic vulnerabilities that arise from SWI/SNF gene mutations is leading to new areas of clinical investigation, including studies of immunotherapy in addition to kinase inhibitors and agents targeting mediators of DNA damage repair.

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Fig. 1: Function of SWI/SNF chromatin-remodelling complexes.
Fig. 2: Frequency and pattern of SWI/SNF subunit mutations across human cancers.
Fig. 3: Translational science of cancers with SWI/SNF complex aberrations.

References

  1. Shain, A. H. & Pollack, J. R. The spectrum of SWI/SNF mutations, ubiquitous in human cancers. PLoS One 8, e55119 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  2. Kadoch, C. et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat. Genet. 45, 592–601 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  4. Roberts, C. W., Leroux, M. M., Fleming, M. D. & Orkin, S. H. Highly penetrant, rapid tumorigenesis through conditional inversion of the tumor suppressor gene Snf5. Cancer Cell 2, 415–425 (2002).

    CAS  PubMed  Article  Google Scholar 

  5. Wiegand, K. C. et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N. Engl. J. Med. 363, 1532–1543 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. Jones, S. et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228–231 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Clapier, C. R. & Cairns, B. R. The biology of chromatin remodeling complexes. Annu. Rev. Biochem. 78, 273–304 (2009).

    CAS  PubMed  Article  Google Scholar 

  9. Wilson, B. G. & Roberts, C. W. SWI/SNF nucleosome remodellers and cancer. Nat. Rev. Cancer 11, 481–492 (2011).

    CAS  PubMed  Article  Google Scholar 

  10. Euskirchen, G., Auerbach, R. K. & Snyder, M. SWI/SNF chromatin-remodeling factors: multiscale analyses and diverse functions. J. Biol. Chem. 287, 30897–30905 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Kwon, H., Imbalzano, A. N., Khavari, P. A., Kingston, R. E. & Green, M. R. Nucleosome disruption and enhancement of activator binding by a human SW1/SNF complex. Nature 370, 477–481 (1994).

    CAS  PubMed  Article  Google Scholar 

  12. Wang, W. et al. Purification and biochemical heterogeneity of the mammalian SWI-SNF complex. EMBO J. 15, 5370–5382 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Lemon, B., Inouye, C., King, D. S. & Tjian, R. Selectivity of chromatin-remodelling cofactors for ligand-activated transcription. Nature 414, 924–928 (2001).

    CAS  PubMed  Article  Google Scholar 

  14. Raab, J. R., Resnick, S. & Magnuson, T. Genome-wide transcriptional regulation mediated by biochemically distinct SWI/SNF complexes. PLoS Genet. 11, e1005748 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    PubMed  PubMed Central  Article  Google Scholar 

  17. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. Mashtalir, N. et al. Modular organization and assembly of SWI/SNF family chromatin remodeling complexes. Cell 175, 1272–1288.e20 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Cairns, B. R., Kim, Y. J., Sayre, M. H., Laurent, B. C. & Kornberg, R. D. A multisubunit complex containing the SWI1/ADR6, SWI2/SNF2, SWI3, SNF5, and SNF6 gene products isolated from yeast. Proc. Natl Acad. Sci. USA 91, 1950–1954 (1994).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. Neigeborn, L. & Carlson, M. Genes affecting the regulation of SUC2 gene expression by glucose repression in Saccharomyces cerevisiae. Genetics 108, 845–858 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Stern, M., Jensen, R. & Herskowitz, I. Five SWI genes are required for expression of the HO gene in yeast. J. Mol. Biol. 178, 853–868 (1984).

    CAS  PubMed  Article  Google Scholar 

  23. Martens, J. A., Wu, P. Y. & Winston, F. Regulation of an intergenic transcript controls adjacent gene transcription in Saccharomyces cerevisiae. Genes Dev. 19, 2695–2704 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Mathur, R. et al. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat. Genet. 49, 296–302 (2017).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  26. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Alver, B. H. et al. The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers. Nat. Commun. 8, 14648 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  28. Lu, C. & Allis, C. D. SWI/SNF complex in cancer. Nat. Genet. 49, 178–179 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Gatchalian, J. et al. A non-canonical BRD9-containing BAF chromatin remodeling complex regulates naive pluripotency in mouse embryonic stem cells. Nat. Commun. 9, 5139 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. Hodges, C., Kirkland, J. G. & Crabtree, G. R. The many roles of BAF (mSWI/SNF) and PBAF complexes in cancer. Cold Spring Harb. Perspect. Med. 6, a026930 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. Ogiwara, H. et al. Histone acetylation by CBP and p300 at double-strand break sites facilitates SWI/SNF chromatin remodeling and the recruitment of non-homologous end joining factors. Oncogene 30, 2135–2146 (2011).

    CAS  PubMed  Article  Google Scholar 

  32. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Chen, Y. et al. A PARP1–BRG1–SIRT1 axis promotes HR repair by reducing nucleosome density at DNA damage sites. Nucleic Acids Res. 47, 8563–8580 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 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).

    CAS  PubMed  Article  Google Scholar 

  35. Chabanon, R. M., Morel, D. & Postel-Vinay, S. Exploiting epigenetic vulnerabilities in solid tumors: novel therapeutic opportunities in the treatment of SWI/SNF-defective cancers. Semin. Cancer Biol. 61,180–198 (2019).

    PubMed  Article  CAS  Google Scholar 

  36. Watanabe, R. et al. SWI/SNF factors required for cellular resistance to DNA damage include ARID1A and ARID1B and show interdependent protein stability. Cancer Res. 74, 2465–2475 (2014).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Shen, J. et al. ARID1A deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors. Cancer Discov. 5, 752–767 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Dykhuizen, E. C. et al. BAF complexes facilitate decatenation of DNA by topoisomerase IIalpha. Nature 497, 624–627 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Zhao, B. et al. ARID1A promotes genomic stability through protecting telomere cohesion. Nat. Commun. 10, 4067 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  41. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Brownlee, P. M., Chambers, A. L., Cloney, R., Bianchi, A. & Downs, J. A. BAF180 promotes cohesion and prevents genome instability and aneuploidy. Cell Rep. 6, 973–981 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Biegel, J. A. et al. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 59, 74–79 (1999).

    CAS  PubMed  Google Scholar 

  44. Sevenet, N. et al. Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am. J. Hum. Genet. 65, 1342–1348 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Finetti, M. A., Grabovska, Y., Bailey, S. & Williamson, D. Translational genomics of malignant rhabdoid tumours: current impact and future possibilities. Semin. Cancer Biol.61, 20–41 (2020).

    Article  CAS  Google Scholar 

  46. Roberts, C. W., Galusha, S. A., McMenamin, M. E., Fletcher, C. D. & Orkin, S. H. Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid tumors in mice. Proc. Natl Acad. Sci. USA 97, 13796–13800 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. Guidi, C. J. et al. Disruption of Ini1 leads to peri-implantation lethality and tumorigenesis in mice. Mol. Cell Biol. 21, 3598–3603 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Klochendler-Yeivin, A. et al. The murine SNF5/INI1 chromatin remodeling factor is essential for embryonic development and tumor suppression. EMBO Rep. 1, 500–506 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Han, Z. Y. et al. The occurrence of intracranial rhabdoid tumours in mice depends on temporal control of Smarcb1 inactivation. Nat. Commun. 7, 10421 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Brennan, B., Stiller, C. & Bourdeaut, F. Extracranial rhabdoid tumours: what we have learned so far and future directions. Lancet Oncol. 14, e329–e336 (2013).

    PubMed  Article  Google Scholar 

  51. Hasselblatt, M. et al. SMARCA4-mutated atypical teratoid/rhabdoid tumors are associated with inherited germline alterations and poor prognosis. Acta Neuropathol. 128, 453–456 (2014).

    PubMed  Article  Google Scholar 

  52. Lu, B. & Shi, H. An in-depth look at small cell carcinoma of the ovary, hypercalcemic type (SCCOHT): clinical implications from recent molecular findings. J. Cancer 10, 223–237 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 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).

    CAS  PubMed  Article  Google Scholar 

  54. Kahali, B. et al. The silencing of the SWI/SNF subunit and anticancer gene BRM in rhabdoid tumors. Oncotarget 5, 3316–3332 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  55. Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).

    PubMed  Article  Google Scholar 

  56. Sima, X. et al. The genetic alteration spectrum of the SWI/SNF complex: the oncogenic roles of BRD9 and ACTL6A. PLoS One 14, e0222305 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Hu, Z. et al. Genomic characterization of genes encoding histone acetylation modulator proteins identifies therapeutic targets for cancer treatment. Nat. Commun. 10, 733 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Hodges, H. C. et al. Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers. Nat. Struct. Mol. Biol. 25, 61–72 (2018).

    CAS  PubMed  Article  Google Scholar 

  59. Gu, Y. F. et al. Modeling renal cell carcinoma in mice: Bap1 and Pbrm1 inactivation drive tumor grade. Cancer Discov. 7, 900–917 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Bultman, S. J. et al. Characterization of mammary tumors from Brg1 heterozygous mice. Oncogene 27, 460–468 (2008).

    CAS  PubMed  Article  Google Scholar 

  61. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Tsurusaki, Y. et al. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nat. Genet. 44, 376–378 (2012).

    CAS  PubMed  Article  Google Scholar 

  64. Van Houdt, J. K. et al. Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome. Nat. Genet. 44, 445–449, S1 (2012).

    PubMed  Article  CAS  Google Scholar 

  65. Orlando, K. A., Nguyen, V., Raab, J. R., Walhart, T. & Weissman, B. E. Remodeling the cancer epigenome: mutations in the SWI/SNF complex offer new therapeutic opportunities. Expert Rev. Anticancer Ther. 19, 375–391 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Stern, C. Boveri and the early days of genetics. Nature 166, 446 (1950).

    CAS  PubMed  Article  Google Scholar 

  67. Lazzerini-Denchi, E. & Sfeir, A. Stop pulling my strings — what telomeres taught us about the DNA damage response. Nat. Rev. Mol. Cell Biol. 17, 364–378 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Li, S. K. H. & Martin, A. Mismatch repair and colon cancer: mechanisms and therapies explored. Trends Mol. Med. 22, 274–289 (2016).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. Lawrence, M. S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. Creighton, C. J. et al. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013).

    CAS  Article  Google Scholar 

  72. Ramos, P. et al. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nat. Genet. 46, 427–429 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. Yates, L. R. et al. Genomic evolution of breast cancer metastasis and relapse. Cancer Cell 32, 169–184.e7 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Gibson, W. J. et al. The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis. Nat. Genet. 48, 848–855 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Betz, B. L., Strobeck, M. W., Reisman, D. N., Knudsen, E. S. & Weissman, B. E. Re-expression of hSNF5/INI1/BAF47 in pediatric tumor cells leads to G1 arrest associated with induction of p16ink4a and activation of RB. Oncogene 21, 5193–5203 (2002).

    CAS  PubMed  Article  Google Scholar 

  76. Wang, X. et al. TCR-dependent transformation of mature memory phenotype T cells in mice. J. Clin. Invest. 121, 3834–3845 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. Look, A. T. Oncogenic transcription factors in the human acute leukemias. Science 278, 1059–1064 (1997).

    CAS  PubMed  Article  Google Scholar 

  78. Andersson, A. K. et al. The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias. Nat. Genet. 47, 330–337 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. Huether, R. et al. The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nat. Commun. 5, 3630 (2014).

    PubMed  Article  CAS  Google Scholar 

  80. van der Weyden, L. et al. Somatic drivers of B-ALL in a model of ETV6-RUNX1; Pax5+/– leukemia. BMC Cancer 15, 585 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  81. Aster, J. C. et al. Essential roles for ankyrin repeat and transactivation domains in induction of T-cell leukemia by notch1. Mol. Cell Biol. 20, 7505–7515 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Adams, J. M. et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318, 533–538 (1985).

    CAS  PubMed  Article  Google Scholar 

  83. Condorelli, G. L. et al. T-cell-directed TAL-1 expression induces T-cell malignancies in transgenic mice. Cancer Res. 56, 5113–5119 (1996).

    CAS  PubMed  Google Scholar 

  84. Peterson, C. L. & Herskowitz, I. Characterization of the yeast SWI1, SWI2, and SWI3 genes, which encode a global activator of transcription. Cell 68, 573–583 (1992).

    CAS  PubMed  Article  Google Scholar 

  85. Savas, S. & Skardasi, G. The SWI/SNF complex subunit genes: their functions, variations, and links to risk and survival outcomes in human cancers. Crit. Rev. Oncol. Hematol. 123, 114–131 (2018).

    PubMed  Article  Google Scholar 

  86. Endo, M. et al. Alterations of the SWI/SNF chromatin remodelling subunit-BRG1 and BRM in hepatocellular carcinoma. Liver Int. 33, 105–117 (2013).

    CAS  PubMed  Article  Google Scholar 

  87. Cho, H. et al. Loss of ARID1A/BAF250a expression is linked to tumor progression and adverse prognosis in cervical cancer. Hum. Pathol. 44, 1365–1374 (2013).

    CAS  PubMed  Article  Google Scholar 

  88. Faraj, S. F. et al. ARID1A immunohistochemistry improves outcome prediction in invasive urothelial carcinoma of urinary bladder. Hum. Pathol. 45, 2233–2239 (2014).

    CAS  PubMed  Article  Google Scholar 

  89. Bai, J. et al. BRG1 is a prognostic marker and potential therapeutic target in human breast cancer. PLoS One 8, e59772 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. Kaufmann, B. et al. BRG1 promotes hepatocarcinogenesis by regulating proliferation and invasiveness. PLoS One 12, e0180225 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  91. Zhu, P. et al. LncBRM initiates YAP1 signalling activation to drive self-renewal of liver cancer stem cells. Nat. Commun. 7, 13608 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. Agaimy, A. SWI/SNF complex-deficient soft tissue neoplasms: a pattern-based approach to diagnosis and differential diagnosis. Surg. Pathol. Clin. 12, 149–163 (2019).

    PubMed  Article  Google Scholar 

  93. Hadfield, K. D. et al. Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis. J. Med. Genet. 45, 332–339 (2008).

    CAS  PubMed  Article  Google Scholar 

  94. Smith, M. J. et al. Expression of SMARCB1 (INI1) mutations in familial schwannomatosis. Hum. Mol. Genet. 21, 5239–5245 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. Smith, M. J., Wallace, A. J., Bowers, N. L., Eaton, H. & Evans, D. G. SMARCB1 mutations in schwannomatosis and genotype correlations with rhabdoid tumors. Cancer Genet. 207, 373–378 (2014).

    CAS  PubMed  Article  Google Scholar 

  96. Bourdeaut, F. et al. Frequent hSNF5/INI1 germline mutations in patients with rhabdoid tumor. Clin. Cancer Res. 17, 31–38 (2011).

    CAS  PubMed  Article  Google Scholar 

  97. Anaya, J., Reon, B., Chen, W. M., Bekiranov, S. & Dutta, A. A pan-cancer analysis of prognostic genes. PeerJ 3, e1499 (2015).

    PubMed  Article  CAS  Google Scholar 

  98. Agaimy, A. & Foulkes, W. D. Hereditary SWI/SNF complex deficiency syndromes. Semin. Diagn. Pathol. 35, 193–198 (2018).

    PubMed  Article  Google Scholar 

  99. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. Ntziachristos, P. et al. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat. Med. 18, 298–301 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. Gibson, W. T. et al. Mutations in EZH2 cause Weaver syndrome. Am. J. Hum. Genet. 90, 110–118 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. Helming, K. C. et al. ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nat. Med. 20, 251–254 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. Wang, X. et al. Oncogenesis caused by loss of the SNF5 tumor suppressor is dependent on activity of BRG1, the ATPase of the SWI/SNF chromatin remodeling complex. Cancer Res. 69, 8094–8101 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. Hoffman, G. R. et al. Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers. Proc. Natl Acad. Sci. USA 111, 3128–3133 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  105. Oike, T. et al. A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. Cancer Res. 73, 5508–5518 (2013).

    CAS  PubMed  Article  Google Scholar 

  106. Papillon, J. P. N. et al. Discovery of orally active inhibitors of brahma homolog (BRM)/SMARCA2 ATPase activity for the treatment of brahma related gene 1 (BRG1)/SMARCA4-mutant cancers. J. Med. Chem. 61, 10155–10172 (2018).

    CAS  PubMed  Article  Google Scholar 

  107. Farnaby, W. et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat. Chem. Biol. 15, 672–680 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. Winter, G. E. et al. Drug development. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348, 1376–1381 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. Zengerle, M., Chan, K. H. & Ciulli, A. Selective small molecule induced degradation of the BET bromodomain protein BRD4. ACS Chem. Biol. 10, 1770–1777 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. Lu, J. et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem. Biol. 22, 755–763 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. Reisman, D. N., Sciarrotta, J., Wang, W., Funkhouser, W. K. & Weissman, B. E. Loss of BRG1/BRM in human lung cancer cell lines and primary lung cancers: correlation with poor prognosis. Cancer Res. 63, 560–566 (2003).

    CAS  PubMed  Google Scholar 

  112. Shorstova, T. et al. SWI/SNF-compromised cancers are susceptible to bromodomain inhibitors. Cancer Res. 79, 2761–2774 (2019).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. Theodoulou, N. H. et al. Discovery of I-BRD9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition. J. Med. Chem. 59, 1425–1439 (2016).

    CAS  PubMed  Article  Google Scholar 

  115. Kennison, J. A. & Tamkun, J. W. Dosage-dependent modifiers of polycomb and antennapedia mutations in Drosophila. Proc. Natl Acad. Sci. USA 85, 8136–8140 (1988).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  116. Tamkun, J. W. et al. Brahma: a regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2. Cell 68, 561–572 (1992).

    CAS  PubMed  Article  Google Scholar 

  117. Wilson, B. G. et al. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell 18, 316–328 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. Erkek, S. et al. Comprehensive analysis of chromatin states in atypical teratoid/rhabdoid tumor identifies diverging roles for SWI/SNF and polycomb in gene regulation. Cancer Cell 35, 95–110.e8 (2019).

    CAS  PubMed  Article  Google Scholar 

  119. Kadoch, C. et al. Dynamics of BAF-polycomb complex opposition on heterochromatin in normal and oncogenic states. Nat. Genet. 49, 213–222 (2017).

    CAS  PubMed  Article  Google Scholar 

  120. Kim, K. H. et al. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat. Med. 21, 1491–1496 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. Kim, K. H. & Roberts, C. W. Targeting EZH2 in cancer. Nat. Med. 22, 128–134 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. Knutson, S. K. et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat. Chem. Biol. 8, 890–896 (2012).

    CAS  PubMed  Article  Google Scholar 

  123. Italiano, A. et al. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol. 19, 649–659 (2018).

    CAS  PubMed  Article  Google Scholar 

  124. Kawano, S. et al. Preclinical evidence of anti-tumor activity induced by EZH2 inhibition in human models of synovial sarcoma. PLoS One 11, e0158888 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  125. Kurmasheva, R. T. et al. Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the pediatric preclinical testing program. Pediatr. Blood Cancer 64, 26218 (2017).

    Article  CAS  Google Scholar 

  126. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  127. Le Loarer, F. et al. Consistent SMARCB1 homozygous deletions in epithelioid sarcoma and in a subset of myoepithelial carcinomas can be reliably detected by FISH in archival material. Genes Chromosomes Cancer 53, 475–486 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. Maruyama, D. et al. First-in-human study of the EZH1/2 dual inhibitor DS-3201b in patients with relapsed or refractory non-Hodgkin lymphomas — preliminary results. Blood 130, 4070–4070 (2017).

    Google Scholar 

  129. Mohammad, H. P., Barbash, O. & Creasy, C. L. Targeting epigenetic modifications in cancer therapy: erasing the roadmap to cancer. Nat. Med. 25, 403–418 (2019).

    CAS  PubMed  Article  Google Scholar 

  130. Torchia, J. et al. Integrated (epi)-genomic analyses identify subgroup-specific therapeutic targets in CNS rhabdoid tumors. Cancer Cell 30, 891–908 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. Knipstein, J. A. et al. Histone deacetylase inhibition decreases proliferation and potentiates the effect of ionizing radiation in atypical teratoid/rhabdoid tumor cells. Neuro Oncol. 14, 175–183 (2012).

    CAS  PubMed  Article  Google Scholar 

  132. Fukumoto, T. et al. Repurposing pan-HDAC inhibitors for ARID1A-mutated ovarian cancer. Cell Rep. 22, 3393–3400 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 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).

    CAS  PubMed  Article  Google Scholar 

  134. Ho, B. et al. Molecular subgrouping of atypical teratoid/rhabdoid tumors (ATRT) — a reinvestigation and current consensus. Neuro Oncol. https://doi.org/10.1093/neuonc/noz235 (2019).

  135. Chun, H. E. et al. Genome-wide profiles of extra-cranial malignant rhabdoid tumors reveal heterogeneity and dysregulated developmental pathways. Cancer Cell 29, 394–406 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. Weissmiller, A. M. et al. Inhibition of MYC by the SMARCB1 tumor suppressor. Nat. Commun. 10, 2014 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  137. Jagani, Z. et al. Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway. Nat. Med. 16, 1429–1433 (2010).

    CAS  PubMed  Article  Google Scholar 

  138. Alimova, I. et al. Inhibition of MYC attenuates tumor cell self-renewal and promotes senescence in SMARCB1-deficient group 2 atypical teratoid rhabdoid tumors to suppress tumor growth in vivo. Int. J. Cancer 144, 1983–1995 (2019).

    CAS  PubMed  Article  Google Scholar 

  139. Venkataraman, S. et al. Targeting aurora kinase A enhances radiation sensitivity of atypical teratoid rhabdoid tumor cells. J. Neurooncol 107, 517–526 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. Xue, Y. et al. SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer. Nat. Commun. 10, 557 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. Xue, Y. et al. CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary. Nat. Commun. 10, 558 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. Tagal, V. et al. SMARCA4-inactivating mutations increase sensitivity to aurora kinase A inhibitor VX-680 in non-small cell lung cancers. Nat. Commun. 8, 14098 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. Geoerger, B. et al. A phase I study of the CDK4/6 inhibitor ribociclib (LEE011) in pediatric patients with malignant rhabdoid tumors, neuroblastoma, and other solid tumors. Clin. Cancer Res. 23, 2433–2441 (2017).

    CAS  PubMed  Article  Google Scholar 

  144. Mosse, Y. P. et al. A phase II study of alisertib in children with recurrent/refractory solid tumors or leukemia: Children’s Oncology Group Phase I and pilot consortium (ADVL0921). Clin. Cancer Res. 25, 3229–3238 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  145. Oberlick, E. M. et al. Small-molecule and CRISPR screening converge to reveal receptor tyrosine kinase dependencies in pediatric rhabdoid tumors. Cell Rep. 28, 2331–2344.e8 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  146. Chauvin, C. et al. High-throughput drug screening identifies pazopanib and clofilium tosylate as promising treatments for malignant rhabdoid tumors. Cell Rep. 21, 1737–1745 (2017).

    CAS  PubMed  Article  Google Scholar 

  147. Wong, J. P. et al. Dual targeting of PDGFRalpha and FGFR1 displays synergistic efficacy in malignant rhabdoid tumors. Cell Rep. 17, 1265–1275 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. Miller, R. E. et al. Synthetic lethal targeting of ARID1A-mutant ovarian clear cell tumors with dasatinib. Mol. Cancer Ther. 15, 1472–1484 (2016).

    CAS  PubMed  Article  Google Scholar 

  149. Lang, J. D. et al. Ponatinib shows potent antitumor activity in small cell carcinoma of the ovary hypercalcemic type (SCCOHT) through multikinase inhibition. Clin. Cancer Res. 24, 1932–1943 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  150. Yamamoto, S., Tsuda, H., Takano, M., Tamai, S. & Matsubara, O. PIK3CA mutations and loss of ARID1A protein expression are early events in the development of cystic ovarian clear cell adenocarcinoma. Virchows Arch. 460, 77–87 (2012).

    CAS  PubMed  Article  Google Scholar 

  151. Bosse, T. et al. Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer. Mod. Pathol. 26, 1525–1535 (2013).

    CAS  PubMed  Article  Google Scholar 

  152. St Pierre, R. & Kadoch, C. Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities. Curr. Opin. Genet. Dev. 42, 56–67 (2017).

    CAS  Article  Google Scholar 

  153. Samartzis, E. P. et al. Loss of ARID1A expression sensitizes cancer cells to PI3K- and AKT-inhibition. Oncotarget 5, 5295–5303 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  154. Dal Molin, M. et al. Loss of expression of the SWI/SNF chromatin remodeling subunit BRG1/SMARCA4 is frequently observed in intraductal papillary mucinous neoplasms of the pancreas. Hum. Pathol. 43, 585–591 (2012).

    CAS  PubMed  Article  Google Scholar 

  155. Zhang, Q. et al. Chromatin remodeling gene AT-rich interactive domain-containing protein 1A suppresses gastric cancer cell proliferation by targeting PIK3CA and PDK1. Oncotarget 7, 46127–46141 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  156. Yap, T. A., Bjerke, L., Clarke, P. A. & Workman, P. Drugging PI3K in cancer: refining targets and therapeutic strategies. Curr. Opin. Pharmacol. 23, 98–107 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. Ding, Y. et al. Chromatin remodeling ATPase BRG1 and PTEN are synthetic lethal in prostate cancer. J. Clin. Invest. 129, 759–773 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  158. Howard, T. P. et al. MDM2 and MDM4 are therapeutic vulnerabilities in malignant rhabdoid tumors. Cancer Res. 79, 2404–2414 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. Carugo, A. et al. p53 is a master regulator of proteostasis in SMARCB1-deficient malignant rhabdoid tumors. Cancer Cell 35, 204–220.e9 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  160. Williamson, C. T. et al. ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A. Nat. Commun. 7, 13837 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. Park, Y. et al. Loss of ARID1A in tumor cells renders selective vulnerability to combined ionizing radiation and PARP inhibitor therapy. Clin. Cancer Res. 25, 5584–5594 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. Miao, D. et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359, 801–806 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. Pan, D. et al. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science 359, 770–775 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  164. Shen, J. et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat. Med. 24, 556–562 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. Ashizawa, M. et al. Prognostic role of ARID1A negative expression in gastric cancer. Sci. Rep. 9, 6769 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  166. Buglioni, S. et al. The clinical significance of PD-L1 in advanced gastric cancer is dependent on ARID1A mutations and ATM expression. Oncoimmunology 7, e1457602 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  167. Kim, Y. B., Ahn, J. M., Bae, W. J., Sung, C. O. & Lee, D. Functional loss of ARID1A is tightly associated with high PD-L1 expression in gastric cancer. Int. J. Cancer 145, 916–926 (2019).

    CAS  PubMed  Article  Google Scholar 

  168. Jiang, T., Chen, X., Su, C., Ren, S. & Zhou, C. Pan-cancer analysis of ARID1A alterations as biomarkers for immunotherapy outcomes. J. Cancer 11, 776–780 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. Leruste, A. et al. Clonally expanded t cells reveal immunogenicity of rhabdoid tumors. Cancer Cell36, 597–612 (2019).

    CAS  PubMed  Article  Google Scholar 

  170. Chun, H. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  171. Forrest, S. J. et al. Genomic and immunologic characterization of INI1-deficient pediatric cancers. Clin. Cancer Res. 26, CCR-19-3089 (2020).

    Article  Google Scholar 

  172. Jelinic, P. et al. Immune-active microenvironment in small cell carcinoma of the ovary, hypercalcemic type: rationale for immune checkpoint blockade. J. Natl Cancer Inst. 110, 787–790 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  173. McDermott, D. F. et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat. Med. 24, 749–757 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. Keenan, T. E., Burke, K. P. & Van Allen, E. M. Genomic correlates of response to immune checkpoint blockade. Nat. Med. 25, 389–402 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  175. Schick, S. et al. Systematic characterization of BAF mutations provides insights into intracomplex synthetic lethalities in human cancers. Nat. Genet. 51, 1399–1410 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

The work of C.W.M.R. is supported by grants from the US National Institutes of Health (R01CA172152 and R01CA113794), Cure AT/RT Now, the Avalanna Fund, the Garrett B. Smith Foundation and American Lebanese Syrian Associated Charities (ALSAC) of the St. Jude Children’s Research Hospital. The authors thank S. Throm of the St. Jude Children’s Research Hospital for her insights and K. A. Laycock, also of the St. Jude Children’s Research Hospital, for scientific editing of the manuscript.

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Nature Reviews Clinical Oncology thanks Michael C. Frühwald and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Mittal, P., Roberts, C.W.M. The SWI/SNF complex in cancer — biology, biomarkers and therapy. Nat Rev Clin Oncol 17, 435–448 (2020). https://doi.org/10.1038/s41571-020-0357-3

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