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Molecular and Cellular Biology, October 2008, p. 6223-6233, Vol. 28, No. 20
0270-7306/08/$08.00+0 doi:10.1128/MCB.00658-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Loss of the Epigenetic Tumor Suppressor SNF5 Leads to Cancer without Genomic Instability
,
Elizabeth S. McKenna,1,
Courtney G. Sansam,1,
Yoon-Jae Cho,2
Heidi Greulich,3
Julia A. Evans,1
Christopher S. Thom,1
Lisa A. Moreau,4
Jaclyn A. Biegel,5
Scott L. Pomeroy,2 and
Charles W. M. Roberts1*
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115,1 Department of Neurology, Children's Hospital Boston, Boston, Massachusetts 02115,2 Department of Medical Oncology, Dana-Farber Cancer Institute and Eli and Edythe L. Broad Institute, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts 02142,3 Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115,4 Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 191045
Received 22 April 2008/ Returned for modification 10 June 2008/ Accepted 4 August 2008
There is a growing appreciation of the role that epigenetic alterations can play in oncogenesis. However, given the large number of genetic anomalies present in most cancers, it has been difficult to evaluate the extent to which epigenetic changes contribute to cancer. SNF5 (INI1/SMARCB1/BAF47) is a tumor suppressor that regulates the epigenome as a core member of the SWI/SNF chromatin remodeling complex. While the SWI/SNF complex displays potent tumor suppressor activity, it is unknown whether this activity is exerted genetically via maintenance of genome integrity or epigenetically via transcriptional regulation. Here we show that Snf5-deficient primary cells do not show altered sensitivity to DNA damaging agents, defects in 
-H2AX induction, or an abrogated DNA damage checkpoint. Further, the aggressive malignancies that arise following SNF5 loss are diploid and genomically stable. Remarkably, we demonstrate that most human SNF5-deficient cancers lack genomic amplifications/deletions and, aside from SNF5 loss, are indistinguishable from normal cells on single-nucleotide polymorphism arrays. Finally, we show that epigenetically based changes in transcription that occur following SNF5 loss correlate with the tumor phenotype. Collectively, our results provide novel insight into the mechanisms of oncogenesis by demonstrating that disruption of a chromatin remodeling complex can largely, if not completely, substitute for genomic instability in the genesis of aggressive cancer.
* Corresponding author. Mailing address: Dana-Farber Cancer Institute, 44 Binney Street-Mayer 657, Boston, MA 02115. Phone: (617) 632-6497. Fax: (617) 582-8096. E-mail: charles_roberts{at}dfci.harvard.edu
Published ahead of print on 18 August 2008.
Supplemental material for this article may be found at http://mcb.asm.org/.
These authors contributed equally to this work.
Molecular and Cellular Biology, October 2008, p. 6223-6233, Vol. 28, No. 20
0270-7306/08/$08.00+0 doi:10.1128/MCB.00658-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
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