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Two novel BRM insertion promoter sequence variants are associated with loss of BRM expression and lung cancer risk

Oncogene volume 30, pages 3295–3304 (2011)Cite this article

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Abstract

SWI/SNF (SWItch/sucrose non-fermentable) complexes are ATP-dependent chromatin remodeling enzymes critically involved in the regulation of multiple functions, including gene expression, differentiation, development, DNA repair, cell adhesion and cell cycle control. BRM, a key SWI/SNF complex subunit, is silenced in 15–20% of many solid tumors. As BRM-deficient mice develop 10-fold more tumors when exposed to carcinogens, BRM is a strong candidate for a cancer susceptibility gene. In this paper, we show that BRM is regulated by transcription, thus demonstrating that the promoter region is important for BRM expression. We sequenced the BRM promoter region, finding two novel promoter indel polymorphisms, BRM −741 and BRM −1321, that are in linkage disequilibrium (D′⩾0.83). The variant insertion alleles of both polymorphisms produce sequence variants that are highly homologous to myocyte enhancer factor-2 (MEF2) transcription factor-binding sites; MEF2 is known to recruit histone deacetylases that silence BRM expression. Each polymorphic BRM insertion variant is found in ∼20% of Caucasians, and each correlates strongly with the loss of protein expression of BRM, both in cancer cell lines (P=0.009) and in primary human lung tumor specimens (P=0.015). With such strong functional evidence, we conducted a case–control study of 1199 smokers. We found an increased risk of lung cancer when both BRM homozygous promoter insertion variants were present: adjusted odds ratio of 2.19 (95% confidence interval, 1.40–3.43). Thus, we here demonstrate a strong functional association between these polymorphisms and loss of BRM expression. These polymorphisms thus have the potential to identify a sub-population of smokers at greater lung cancer risk, wherein this risk could be driven by an aberrant SWI/SNF chromatin-remodeling pathway.

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Acknowledgements

GL is funded by the Alan B Brown Chair in Molecular Genomics, CCO Chair in Experimental Therapeutics and Population Studies, and Posluns Family Foundation; FAS holds the Scott Taylor Chair in Lung Cancer Research; MST holds the M Qasim Chair in Lung Cancer Translational Research; Supported by the Ontario Ministry of Health and Long Term Care (OMHLTC) and the Lucy Wong Fund. The results presented do not necessarily reflect the views of OMHLTC. Reisman lab funding is from NCI:7R03CA128038-02.

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Author notes

  1. G Liu and S Gramling: These authors contributed equally to this publication and should be considered first authors.

Authors and Affiliations

  1. Department of Medicine, Division of Medical Oncology and Hematology, Ontario Cancer Institute, Princess Margaret Hospital-University Health Network, University of Toronto, Toronto, Ontario, Canada

    G Liu & F A Shepherd

  2. Department of Medical Biophysics, Ontario Cancer Institute, Princess Margaret Hospital-University Health Network, University of Toronto, Toronto, Ontario, Canada

    G Liu, D Cheng, A K Azad, M Mirshams, Z Chen & M S Tsao

  3. Division of Hematology/Oncology, Department of Medicine, University of Florida, Gainesville, FL, USA

    S Gramling, D Munoz & D Reisman

  4. Biostatistics Department, Ontario Cancer Institute, Princess Margaret Hospital-University Health Network, University of Toronto, Toronto, Ontario, Canada

    W Xu

  5. Department of Radiology, Princess Margaret Hospital-University Health Network, University of Toronto, Toronto, Ontario, Canada

    H Roberts

  6. Department of Pathology and Laboratory Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada

    M S Tsao

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Liu, G., Gramling, S., Munoz, D. et al. Two novel BRM insertion promoter sequence variants are associated with loss of BRM expression and lung cancer risk. Oncogene 30, 3295–3304 (2011). https://doi.org/10.1038/onc.2011.81

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