Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer
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- A. Hunter Shain
- Department of Pathology, Stanford University, Stanford, CA 94305;
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- Craig P. Giacomini
- Department of Pathology, Stanford University, Stanford, CA 94305;
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- Karen Matsukuma
- Department of Pathology, Stanford University, Stanford, CA 94305;
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- Collins A. Karikari
- Departments of bPathology and
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- Murali D. Bashyam
- Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500001, India; and
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- Manuel Hidalgo
- Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231;
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- Anirban Maitra
- Departments of bPathology and
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- Jonathan R. Pollack
- Department of Pathology, Stanford University, Stanford, CA 94305;
書誌事項
- 公開日
- 2011-01-10
- DOI
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- 10.1073/pnas.1114817109
- 公開者
- Proceedings of the National Academy of Sciences
この論文をさがす
説明
<jats:p>Defining the molecular genetic alterations underlying pancreatic cancer may provide unique therapeutic insight for this deadly disease. Toward this goal, we report here an integrative DNA microarray and sequencing-based analysis of pancreatic cancer genomes. Notable among the alterations newly identified, genomic deletions, mutations, and rearrangements recurrently targeted genes encoding components of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex, including all three putative DNA binding subunits (ARID1A, ARID1B, and PBRM1) and both enzymatic subunits (SMARCA2 and SMARCA4). Whereas alterations of each individual SWI/SNF subunit occurred at modest-frequency, as mutational “hills” in the genomic landscape, together they affected at least one-third of all pancreatic cancers, defining SWI/SNF as a major mutational “mountain.” Consistent with a tumor-suppressive role, re-expression of SMARCA4 in SMARCA4-deficient pancreatic cancer cell lines reduced cell growth and promoted senescence, whereas its overexpression in a SWI/SNF-intact line had no such effect. In addition, expression profiling analyses revealed that SWI/SNF likely antagonizes Polycomb repressive complex 2, implicating this as one possible mechanism of tumor suppression. Our findings reveal SWI/SNF to be a central tumor suppressive complex in pancreatic cancer.</jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 109 (5), 252-, 2011-01-10
Proceedings of the National Academy of Sciences
