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

Nature Reviews Clinical Oncology volume 17, pages 435–448 (2020)Cite this article

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.

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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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    Priya Mittal & Charles W. M. Roberts

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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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