Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy

Abstract

Subunits of mammalian SWI/SNF (mSWI/SNF or BAF) complexes have recently been implicated as tumor suppressors in human malignancies. To understand the full extent of their involvement, we conducted a proteomic analysis of endogenous mSWI/SNF complexes, which identified several new dedicated, stable subunits not found in yeast SWI/SNF complexes, including BCL7A, BCL7B and BCL7C, BCL11A and BCL11B, BRD9 and SS18. Incorporating these new members, we determined mSWI/SNF subunit mutation frequency in exome and whole-genome sequencing studies of primary human tumors. Notably, mSWI/SNF subunits are mutated in 19.6% of all human tumors reported in 44 studies. Our analysis suggests that specific subunits protect against cancer in specific tissues. In addition, mutations affecting more than one subunit, defined here as compound heterozygosity, are prevalent in certain cancers. Our studies demonstrate that mSWI/SNF is the most frequently mutated chromatin-regulatory complex (CRC) in human cancer, exhibiting a broad mutation pattern, similar to that of TP53. Thus, proper functioning of polymorphic BAF complexes may constitute a major mechanism of tumor suppression.

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Figure 1: Identification of new, dedicated subunits of mSWI/SNF-like BAF complexes.
Figure 2: mSWI/SNF complex subunit genes are mutated in human cancers with high frequency.
Figure 3: mSWI/SNF complexes are more frequently mutated than other chromatin-modifying complexes in human cancer.
Figure 4: mSWI/SNF subunit genes are more frequently mutated than EP300, MLL and HDAC family genes.
Figure 5: Mutations in mSWI/SNF subunit genes occur in a broad spectrum of cancer types.
Figure 6: Occurrence of multiple mSWI/SNF mutations in human cancers.

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Acknowledgements

This work was supported in part by US National Institutes of Health (NIH) grants NS046789 and CA163915 (both to G.R.C.). G.R.C. is an Investigator of the Howard Hughes Medical Institute. C.K. is supported by the National Science Foundation (Graduate Research Fellowship Program). D.C.H. is supported by a Helen Hay Whitney Foundation Fellowship. C.H. is supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development Fellowship F32HD072627.

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C.K. performed and interpreted experiments. D.C.H. and C.H. performed genomic data analysis and interpretation. L.E., L.H. and J.R. performed proteomic mass spectrometry data collection and analysis. C.K., D.C.H. and G.R.C. conceived of and wrote the manuscript.

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Correspondence to Gerald R Crabtree.

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The authors declare no competing financial interests.

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Supplementary Tables 1–4, 6 and 7, Supplementary Figures 1 and 2, Supplementary Note (PDF 2950 kb)

Supplementary Table 5

Mutation Frequencies (separate Excel Workbook) (XLSX 65 kb)

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Kadoch, C., Hargreaves, D., Hodges, C. et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet 45, 592–601 (2013). https://doi.org/10.1038/ng.2628

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